Compositions and methods for treating depression

ABSTRACT

Disclosed is a therapeutic regimen which includes S-adenosyl methionine, or a salt thereof; folic acid, or a metabolite therof, or a salt thereof; and a compound of Formula (I), or salt thereof, useful in the treatment of a variety of conditions, e.g., neuropsychiatric conditions such as depression. The therapeutic regimen may be used in combination with therapeutic agents as described here.

RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. § 371 ofInternational PCT Application, PCT/US2017/059819, filed Nov. 3, 2017,which claims priority under 35 U.S.C. § 119(e) to U.S. ProvisionalApplication, U.S. Ser. No. 62/417,229, filed Nov. 3, 2016, the entirecontents of each of which is incorporated herein by reference.

BACKGROUND

Behavioral neurology is a subspecialty of neurology that studies theneurological basis of behavior, memory, and cognition, the impact ofneurological damage and disease upon these functions, and the treatmentthereof (see, e.g., Pincus and Tucker, Behavioral Neurology (2^(nd)Edition), Oxford University Press, 1979). Neuropsychiatry is a closelyrelated branch of medicine dealing with mood and mental disordersattributable to diseases of the nervous system (see, e.g., Price et al.,Neurology (2000) 54:8-14). Both fields are involved in treatingconditions which are associated with behavioral dysfunction in humans,such as mood disorders which include depression (e.g., Major DepressiveDisorder), Bipolar Disorder, and Anxiety Disorder, and conditionscharacterized by atypical mood (e.g., depressed mood, irritability,instability of mood, and/or changes in mood), such as stress, hormonalmood swings (e.g., during pregnancy, during post-partum, during puberty,during menopause, or are a result of a Premenstrual Dysphoric Disorderor related condition), Mild Cognitive Impairment, substance-induced mooddisorder (e.g., alcoholism), dementia, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, and psychotic disorders (e.g.,Schizoaffective Disorder, Schizophrenia, Delusional Disorder, andPsychotic Disorder Not Otherwise Specified).

Major Depressive Disorder (MDD) is a neuropsychiatric condition whichafflicts anywhere from 10 to 20% of the population. In the UnitedStates, MDD is a contributing cause to the majority of the approximately30,000 annual deaths by suicide. It has additionally been speculatedthat some unknown proportion of the 100,000 deaths by other unnaturalmeans such as motor vehicle accidents, homicide and workplace accidentsare also related to underlying depressive symptoms. Such deaths are thesixth leading cause of mortality in the United States. Medical treatmentof depression over the years has included the use of psychotherapy andprescription anti-depressants. While generally helpful, these drugs arelimited in their efficacy by their innate toxicity as well as asignificant tendency to unpleasant side effects, such as nausea, sexualdysfunction, cognitive slowing, emotional dulling, lethargy, and sleepdisturbances, as well as potentially dangerous interactions with othermedications. Moreover, in some instances the subject being treated is anon-responder to the prescription anti-depressant therapy. Morerecently, an association has been noted between the use of modern (e.g.,more conventional) prescription anti-depressants and the emergence ofsuicidal ideation, which is observed in a previously non-suicidalpopulation. This risk appears particularly prominent in youngerpatients, e.g., those under the age of 24. This has in turn led toresistance to the use of this class of medication in pediatric,adolescent, and post-adolescent populations. Somewhat ironically, suchunder-treatment may have been associated with a spike in suicide deathsin the under-19 population between 2003 and 2004.

It therefore remains of great interest to explore safer alternatives fortreating neuropsychiatric conditions, especially conditions associatedwith atypical mood, such as depression, e.g., Major Depressive Disorder.

SUMMARY

Nutrients and dietary supplements, sometimes referred to as“nutraceuticals,” represent important alternatives or adjuncts toprescription anti-depressants. Recently, the first systematic(meta-analysis) review of nutraceuticals as adjuncts in the treatment ofdepression was conducted. See Sarris et al., Am. J. Psychiatry (2016)173:575-587, the entire contents of which is incorporated herein byreference. From this comprehensive review of the clinical literature, itwas concluded that SAMe, methyl folate, omega 3-fatty acids(specifically EPA) demonstrate particular promise as adjuncts in thetreatment of depression and other diseases. Furthermore, this uniquetreatment option for depression and other diseases is described in U.S.Pat. No. 9,662,359, issued May 30, 2017 (corresponding to U.S.Publication No. 2013/0330429); and U.S. Pat. No. 8,372,451, issued Feb.12, 2013 (corresponding to U.S. Publication No. 2011/0200690, publishedAug. 18, 2011); the entire contents of each of which are incorporatedherein by reference.

The present disclosure provides compositions, kits, and related methods,that incorporate a combination of therapeutics useful to treat, forexample, neuropsychiatric conditions, such as depression. Thecombination of therapeutics described herein is expected to effectuateboth anti-depressant and mood-stabilizing properties with little to noadverse side effects typically associated with prescriptionanti-depressants. The present disclosure also encompasses use of thetherapy for the administration to subjects not necessarily diagnosedwith a neuropsychiatric condition, such as subjects desiring wellnessand/or energy; subjects having or likely to have coronary arterydisease, liver disease, or osteoarthritis; pregnant subjects; andsubjects having an abnormal folate metabolism due to a metabolicimpairment preventing the absorption of neuroprotective nutrients. Thistherapy may be used therapeutically or prophylactically. In certainembodiments, the composition is designated by the Food and DrugAdministration as a medical food.

In one aspect, provided is a composition comprising S-adenosylmethionine (SAMe), or a salt thereof, and a compound of Formula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkykl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8.In certain embodiments, the composition further comprises folic acid ora salt thereof or an active metabolite thereof (e.g., methyl folate orsalt thereof). In certain embodiments, the composition further comprisesone or more omega-3 fatty acids or salts thereof. In certainembodiments, the composition further comprises vitamin D3.

In another aspect, provided is a composition comprising folic acid, or asalt thereof, or an active metabolite thereof (e.g., methyl folate orsalt thereof), and a compound of Formula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8.In certain embodiments, the composition further comprises S-adenosylmethionine (SAMe) or salt thereof. In certain embodiments, thecomposition further comprises composition one or more omega-3 fattyacids or salts thereof. In certain embodiments, the composition furthercomprises vitamin D3.

In another aspect, provided is a composition comprising one or moreomega-3 fatty acids, or salts thereof, and a compound of Formula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and R_(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8.In certain embodiments, the composition further comprises S-adenosylmethionine (SAMe) or salt thereof. In certain embodiments, thecomposition further comprises folic acid or a salt thereof or an activemetabolite thereof (e.g., methyl folate or salt thereof). In certainembodiments, the composition further comprises vitamin D3.

In another aspect, provided is a composition comprising vitamin D3 and acompound of Formula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8.In certain embodiments, the composition further comprises S-adenosylmethionine (SAMe) or salt thereof. In certain embodiments, thecomposition further comprises folic acid or a salt thereof or an activemetabolite thereof (e.g., methyl folate or salt thereof). In certainembodiments, the composition further comprises one or more omega-3 fattyacids or salts thereof.

In another aspect, provided is a composition comprising a compound ofFormula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8.In certain embodiments, the composition further comprises folic acid ora salt thereof or an active metabolite thereof (e.g., methyl folate orsalt thereof). In certain embodiments, the composition further comprisesS-adenosyl methionine (SAMe) or salt thereof. In certain embodiments,the composition further comprises one or more omega-3 fatty acids orsalts thereof. In certain embodiments, the composition further comprisesvitamin D3.

In certain embodiments, the composition comprises S-adenosyl methionine(SAMe), or a salt thereof; folic acid, or a salt thereof, or an activemetabolite thereof (e.g., methyl folate or salt thereof); and a compoundof Formula (I), or a salt thereof. In certain embodiments, thecomposition further comprises one or more omega-3 fatty acids, or saltsthereof. In certain embodiments, the composition further comprisesvitamin D3.

In certain embodiments, the composition consists essentially ofS-adenosyl methionine (SAMe), or a salt thereof; folic acid, or a saltthereof, or an active metabolite thereof (e.g., methyl folate or saltthereof); and a compound of Formula (I), or a salt thereof. In certainembodiments, the composition consists essentially of S-adenosylmethionine (SAMe), or a salt thereof; folic acid, or a salt thereof, oran active metabolite thereof (e.g., methyl folate or salt thereof); acompound of Formula (I), or a salt thereof; and one or more omega-3fatty acids, or salts thereof. In certain embodiments, the compositionconsists essentially of S-adenosyl methionine (SAMe), or a salt thereof;folic acid, or a salt thereof, or an active metabolite thereof (e.g.,methyl folate or salt thereof); a compound of Formula (I), or a saltthereof; one or more omega-3 fatty acids, or salts thereof; and vitaminD3.

In certain embodiments, the one or more omega-3 fatty acids or saltsthereof comprises at least 50% EPA.

In certain embodiments, the composition is formulated for oraladministration.

In certain embodiments, S-adenosyl methionine, or a salt thereof, isprovided in the composition in a range of between about 200 mg to about2000 mg, inclusive, e.g., in a range of between about 800 mg to about1600 mg, inclusive. In certain embodiments, folic acid, or a saltthereof, or an active metabolite thereof (e.g., methyl folate or saltthereof), is provided in the composition in a range of between about 1mg to about 45 mg, inclusive, e.g., in a range of between about 5 mg toabout 20 mg, inclusive. In certain embodiments, the compound of Formula(I), or salt thereof, is provided in the composition in a range of about50 mg to about 1000 mg, inclusive; e.g., about 100 mg to about 500 mg,inclusive. In certain embodiments, one or more omega-3 fatty acids, orsalts thereof, are provided in the composition in a range of betweenabout 500 mg to about 5 g, inclusive, e.g., between about 800 mg toabout 1600 mg, inclusive. In certain embodiments, vitamin D3 is providedin the composition in a range of between about 500 International Units(IU) to about 2000 International Units (IU), inclusive, e.g., betweenabout 800 IU to about 1500 IU, inclusive; e.g., about 1000 IU.

Other components may be included in the composition. Such additionalcomponents may include, for example, prescription drugs,over-the-counter medicines, and/or vitamins. For example, in certainembodiments, the composition further comprises vitamin B₁₂. In certainembodiments, the vitamin B₁₂ is provided in the composition in a rangeof between about 100 μg to about 1000 μg, inclusive. In certainembodiments, the vitamin B₁₂ is provided in the composition in a rangeof between about 50 μg to about 500 μg, inclusive. In certainembodiments, the composition further comprises St. John's Wort(Hypericum perforatum). However, in certain embodiments, St. John's Wortis specifically excluded.

In certain embodiments, the composition further comprises a prescriptionanti-depressant. In certain embodiments, the compound is administered incombination with a prescription anti-depressant. In certain embodiments,the prescription anti-depressant is selected from the group consistingof selective serotonin reuptake inhibitors (SSRIs), serotonin anddopamine reuptake inhibitors (SDRIs), serotonin-norepinephrine reuptakeinhibitors (SNRIs), serotonin-noradrenaline-dopamine reuptake inhibitors(SNDRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs),norepinephrine (noradrenaline) reuptake inhibitors (NRIs), monoamineoxidase inhibitors (MAOIs), selective serotonin reuptake enhancers(SSREs), melatonergic agonists, tryptamines, tricyclic anti-depressants,and atypical anti-depressants.

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount ofS-adenosyl methionine, or a salt thereof, and a compound of Formula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8,to a subject in need thereof. In certain embodiments, the method furthercomprises administering folic acid, or a salt thereof, or an activemetabolite thereof (e.g., methyl folate or salt thereof). In certainembodiments, the method further comprises administering one or moreomega-3 fatty acids, or salts thereof. In certain embodiments, themethod further comprises administering vitamin D3.

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount offolic acid, or a salt thereof, or an active metabolite thereof (e.g.,methyl folate, or salt thereof), and a compound of Formula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8,to a subject in need thereof. In certain embodiments, the method furthercomprises administering S-adenosyl methionine, or a salt thereof. Incertain embodiments, the method further comprises administering one ormore omega-3 fatty acids, or salts thereof. In certain embodiments, themethod further comprises administering vitamin D3.

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount ofone or more omega-3 fatty acids, or salts thereof and a compound ofFormula (I):

or a salt thereof, wherein R is hydrogen or —C(═)R^(A), wherein R^(A) isunsubstituted C₁₀₋₁₈ alkyl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8,to a subject in need thereof. In certain embodiments, the method furthercomprises administering S-adenosyl methionine, or a salt thereof. Incertain embodiments, the method further comprises administering vitaminD3. In certain embodiments, the method further comprises administeringfolic acid, or a salt thereof, or an active metabolite thereof (e.g.,methyl folate or salt thereof).

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount ofvitamin D3 and a compound of Formula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8,to a subject in need thereof. In certain embodiments, the method furthercomprises administering S-adenosyl methionine, or a salt thereof. Incertain embodiments, the method further comprises administering one ormore omega-3 fatty acids, or salts thereof. In certain embodiments, themethod further comprises administering folic acid, or a salt thereof, oran active metabolite thereof (e.g., methyl folate or salt thereof).

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount of acompound of Formula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8,to a subject in need thereof. In certain embodiments, the method furthercomprises administering S-adenosyl methionine, or a salt thereof. Incertain embodiments, the method further comprises administering one ormore omega-3 fatty acids, or salts thereof. In certain embodiments, themethod further comprises administering folic acid, or a salt thereof, oran active metabolite thereof (e.g., methyl folate or salt thereof). Incertain embodiments, the method further comprises administering vitaminD3. composition

In certain embodiments, the neuropsychiatric condition is a mooddisorder selected from the group consisting of depression, BipolarDisorder, and Anxiety Disorder, or a condition characterized by atypicalmood selected from the group consisting of stress, hormonal mood swings,Mild Cognitive Impairment, substance-induced mood disorders, dementia,Alzheimer's disease, Parkinson's disease, Huntington's disease, andpsychotic disorders.

In certain embodiments, the hormonal mood swings take place duringpregnancy, during post-partum, during puberty, during menopause, or area result of a Premenstrual Dysphoric Disorder or related condition. Incertain embodiments, the substance-induced mood disorder is a mooddisorder induced by alcohol (e.g., alcoholism). In certain embodiments,the psychotic disorder is selected from the group consisting ofSchizoaffective Disorder, Schizophrenia, Delusional Disorder, andPsychotic Disorder Not Otherwise Specified. In certain embodiments,depression is Major Depressive Disorder (MDD). In certain embodiments,the subject is not diagnosed with a Bipolar Disorder. In certainembodiments, the subject has not exhibited an episode of mania. Incertain embodiments, the subject has or is at risk of having an AnxietyDisorder. In certain embodiments, the subject is a post-partum subject(e.g., a lactating post-partum subject).

In certain embodiments, the method comprises administering one or moreof these therapeutic components, as described herein, in separatecompositions. In certain embodiments, the subject is receiving or hasreceived a prescription anti-depressant. In certain embodiments, theprescription anti-depressant is administered with the combination to thesubject in an amount not effective to treat the disorder whenadministered alone. In certain embodiments, the prescriptionanti-depressant causes or is likely to cause an adverse side effect orundesired side effect in the subject. For example, in certainembodiments, the subject is at risk of suicide when administered anSSRI. In certain embodiments, the subject is a non-responder to aprescription anti-depressant.

In certain embodiments, the subject is a mammal, e.g., a domestic mammalor a human. In certain embodiments, the human subject is 24 years of ageor younger. In certain embodiments, the human subject is between the ageof 13 and 24. In certain embodiments, the human subject is between theage of 16 and 24.

In certain embodiments, the method further comprises the step ofmonitoring the effectiveness of the treatment in the subject.

Also provided is a kit comprising one or more of these therapeuticcomponents, as described herein, a container, and instructions for use.In certain embodiments, the kit comprises a 7-day supply, 14-day supply,30-day supply, 60-day supply, or 90-day supply of treatment.

The details of one or more embodiments of the disclosure are set forthin the Detailed Description of Certain Embodiments Section and theExamples as described below. Other features, objects, and advantageswill be apparent from the description and from the claims.

DETAILED DESCRIPTION

The present disclosure is directed to compositions containing a specificcombination of therapeutic components and methods of use thereof,wherein one or more of the therapeutic components provided in thecombination is a complementary and alternative medicine (CAM)therapeutic. “Complementary and alternative medicine” (CAM) broadlyrefers to a non-conventional (e.g., non-prescription) drug-basedtherapies for effectuating improved health. Thus, CAM encompasses agroup of diverse medical and health care systems, practices, andproducts that are not generally considered to be part of conventionalmedicine and includes a number of natural supplements. Complementarymedicine is typically used together with standard medical care, whilealternative medicine is typically used in place of standard medicalcare. The term CAM as used herein embraces both. In certain embodiments,the CAM therapeutic is designated by the Food and Drug Administration asa medical food.

The greater acceptance of non-prescription therapeutics by thetraditional medical community, the perception of corporate bias in drugmarketing, and a general tendency toward non-traditional and non-Westernconcepts of medical diagnosis and treatment have led to the developmentof CAM therapeutics, generally marketed and sold over-the-counter, astreatments for depression as well as other neuropsychiatric conditions,and in recent years, the market for CAM therapeutics has rivaled thesize of the traditional medical marketplace. A neuropsychiatriccondition, as used herein, is a condition associated with behavioraldysfunction in humans, such as atypical mood (e.g., depressed mood,irritability, instability of mood, and/or changes in mood). Exemplaryneuropsychiatric conditions include, but are not limited to, depression(e.g., Major Depressive Disorder), Bipolar Disorder, and AnxietyDisorder, and conditions characterized by atypical mood, such as stress,hormonal mood swings (e.g., during pregnancy, post-partum, PremenstrualDysphoric Disorder and related conditions, puberty, and menopause), MildCognitive Impairment, alcoholism, dementia, Alzheimer's disease,Parkinson's disease, Huntington's disease, and psychotic disorders(e.g., Schizoaffective Disorder, Schizophrenia, Delusional Disorder, andPsychotic Disorder Not Otherwise Specified). It is envisioned that themethods and compositions described herein will be effective for thetreatment of a neuropsychiatric condition.

It is further contemplated that certain therapeutics described herein,e.g., SAMe, or a salt thereof; folic acid, or a salt thereof, or anactive metabolite thereof; and a compound of Formula (I):

or a salt thereof, wherein R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and R^(B) is of the formula:

wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6, 7, or 8;and, optionally, one or more omega-3 fatty acids, or salts thereof;vitamin D3; and/or vitamin B₁₂, when combined is superior to otheranti-depressant therapies. Furthermore, the combination of thesetherapeutic components, as described herein, is expected to causesignificantly less (e.g., little, if any) side effects. For example, thecombinations of therapeutic components described herein can beadministered safely in treating a neuropsychiatric condition, such asdepression, without the risk such as that associated with prescriptionanti-depressant-based therapies. Since one or more of the therapeuticsused in the combination is commercially available and soldover-the-counter without a prescription (i.e., is a CAM therapeutic),the combination has the promise to be a widely accessible, safe,natural, and non-toxic alternative to prescription anti-depressants andmood stabilizers. This combination of agents may further be found usefulin the treatment of subjects which may not have a neuropsychiatriccondition, but would benefit from the therapy. For example, since thetherapy described herein is deemed useful for the treatment of depressedmood, it is also envisioned this combination will be useful in thepromotion of good health, energy, and/or happiness, in a subject (e.g.,a “wellness energy booster”). Since there is a link between coronaryartery disease and depression, it is also envisioned this combinationwill be useful in the treatment of coronary artery disease. Since thereis a link between administration of SAMe and the treatment of liverdisease and the treatment of pain associated with osteoarthritis, it isalso envisioned this combination will be useful in the treatment ofthese diseases. Since folic acid and methyl folate have been found to beuseful in the prevention of neural defects in an embryo or fetus, it isalso envisioned this combination will be useful in the treatment of apregnant or lactating post-partum subject.

S-Adenosyl Methionine

S-Adenosyl methionine (SAMe) is a naturally occurring substance in thehuman body and may also be referred to as S-adenosylmethionine,S-adenosyl-L-methionine, SAM-e®, or SAM herein. SAMe acts as a methyldonor in multiple metabolic processes. The methyl group (CH₃) attachedto the methionine sulfur atom in SAMe is chemically reactive. Thisallows donation of this group to an acceptor substrate intransmethylation reactions.

Another major role of SAMe is in polyamine biosynthesis. In particular,it is involved in the biosynthesis of several hormones andneurotransmitters that affect mood, such as dopamine and serotonin.

In the United States, SAMe is sold as an over-the-counter nutritionalsupplement. SAMe is also marketed under the brand names, GUMBARAL®,SAMYR®, ADOMET®, HEPTRAL® and ADMETHIONINE®, as a prescription drugapproved in Russia, Italy, and Germany.

Some research, including multiple clinical trials, has indicated thattaking SAMe on a regular basis may help treat or prevent depression(see, e.g., Kagan et al., Am. J. Psychiatry (1990) 147:591-595;Rosenbaum et al., Acta Psychiatrica Scandinavica (1990) 81:432-436).SAMe has been demonstrated in double-blind studies to be effective inthe treatment of Major Depressive Disorder (MDD) when administeredeither intravenously or intramuscularly (parenterally). Two out of threedouble-blind studies of oral SAMe have shown efficacy when compared toplacebo in the treatment of Major Depressive Disorder. A third study mayhave utilized an unstable form of the drug and did not demonstrateanti-depressant efficacy. SAMe has been shown to have some effectivenessfor the treatment of liver disease (e.g., pruritus in cholestasis ofpregnancy and intrahepatic cholestasis), and the pain of osteoarthritis(see S-Adenosyl Methionine for Treatment of Depression, Osteoarthritis,and Liver Disease. Evidence Reports/Technology Assessments, October2002, No. 64). Generally, SAMe is well tolerated by most individuals.

Effective amounts of SAMe, or a salt thereof, range from about 200 mg toabout 4000 mg per day for a human subject. In certain embodiments, about200 mg to about 4000 mg of SAMe or a salt thereof per day is useful,e.g., about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg,about 3000 mg or about 4000 mg, per day. In certain embodiments, SAMe ora salt thereof is provided in a range of between about 200 mg to about4000 mg, between about 200 mg to about 2000 mg, between about 400 mg toabout 2000 mg, between 400 mg to about 1000 mg, between about 500 mg toabout 2000 mg, between about 600 mg to about 2000 mg, between about 700mg to about 2000 mg, between about 800 mg to about 2000 mg, betweenabout 800 mg to about 1600 mg, between about 800 to about 1500 mg,between about 800 mg to about 1400 mg, between about 800 mg to about1300 mg, between about 800 mg to about 1200 mg, between about 800 mg toabout 1100 mg, between about 800 mg to about 1000 mg, or between about800 mg to about 900 mg, inclusive. In certain embodiments, the SAMe or asalt thereof is provided in a range of between about 800 mg to about1600 mg. In certain embodiments, the amount of SAMe or a salt thereofadministered per day is about 800 mg, about 1200 mg or about 1600 mg.

Oral SAMe achieves peak plasma concentrations 3 to 5 hours afteringestion of an enteric-coated tablet (e.g., containing between about400 to about 1000 mg) (Najm et al., BMC Musculoskelet. Disord. (2004)5:6). The half-life is about 100 minutes. It may require up to one monthfor it to reach full effectiveness in treating certain conditions.Because of structural instability, stable salt forms of SAMe are usefulin oral compositions. Commonly used salts of SAMe include, withoutlimitation, SAMe tosylate, SAMe butanedisulfonate, SAMe disulfatetosylate, SAMe disulfate ditosylate, and SAMe disulfate monotosylatesalt. However, any salt form of SAMe may be employed in the therapeuticcombination or method.

Folic Acid and Metabolites Thereof

Folic acid and its metabolite methylfolate are substances that arecharacterized as vitamins, essential nutrients available in smallamounts in leafy vegetables and other foods. Folic acid (also known asvitamin B₉ or folacin) and folate (the naturally occurring form), aswell as pteroyl-L-glutamic acid and pteroyl-L-glutamate, are forms ofthe water-soluble vitamin B₉. Folic acid is itself not biologicallyactive, but its biological importance is due to tetrahydrofolate andother derivatives after its conversion to dihydrofolic acid in theliver.

All the biological functions of folic acid are performed bytetrahydrofolate and other derivatives. Their biological availability tothe body depends upon dihydrofolate reductase action in the liver. Thisaction is unusually slow in humans being less than 2% of that in rats.Moreover, in contrast to rats, an almost 5-fold variation in theactivity of this enzyme exists between humans. Due to this low activityit has been suggested that this limits the conversion of folic acid intoits biologically active forms when folic acid is consumed at levelshigher than the Tolerable Upper Intake Level (about 1 mg per day foradults).

In the form of a series of tetrahydrofolate (THF) compounds, folatederivatives are substrates in a number of single-carbon-transferreactions and also are involved in the synthesis of dTMP(2′-deoxythymidine-5′-phosphate) from dUMP(2′-deoxyuridine-5′-phosphate). It is a substrate for an importantreaction that involves vitamin B₁₂. It is necessary for the synthesis ofDNA and so is required for all dividing cells.

The pathway leading to the formation of methyl folate begins when folicacid (F), as folate, is reduced to dihydrofolate (DHF), which is thenreduced to tetrahydrofolate (THF). The enzyme dihydrofolate reductasecatalyses the last step. Vitamin B₃ in the form of NADPH is a necessarycofactor for both steps of the synthesis of DHF and THF.

Methylene-THF (CH₂THF) is formed from THF by the addition of methylenegroups from one of three carbon donors: formaldehyde, serine, orglycine. Methyl folate (CH₃-THF) can be made from methylene-THF byreduction of the methylene group with NADPH. It is important to notethat Vitamin B₁₂ is the only acceptor of methyl-THF. There is also onlyone acceptor for methyl-B₁₂ which is homocysteine in a reactioncatalyzed by homocysteine methyltransferase. This is important because adefect in homocysteine methyltransferase or a deficiency of B12 can leadto a methyl-trap of THF and a subsequent deficiency. Thus, a deficiencyin B₁₂ can generate a large pool of methyl-THF that is unable to undergoreactions and will mimic folate deficiency. Another form of THF,formyl-THF or folinic acid, results from oxidation of methylene-THF oris formed from formate donating a formyl group to THF. Finally,histidine can donate a single carbon to THF to form methenyl-THF.

Folic acid is available as an over-the-counter nutritional supplementand in prescription strength that has been used in the prevention ofneural tube defects in the embryo or fetus of pregnant women. The use offolic acid or methyl folate has caused the near-elimination of theincidence of spina bifida, a devastating congenital birth defect. Thus,the present disclosure contemplates a method of preventive neuraldefects, such as spina bifida, in the embryo or fetus of a pregnantsubject, comprising administering S-adenosyl methionine (SAMe), or asalt thereof; folic acid, or an active metabolite thereof, or a saltthereof; and a compound of Formula (I), or salt thereof, to the pregnantsubject. The disclosure also contemplates a composition comprising theseagents for the prevention of neural tube defects in the embryo or fetusof a pregnant subject.

Both folic acid and methyl folate are, like SAMe, methyl donors inmultiple metabolic processes and have been studied as adjunctive therapyin Major Depressive Disorder. Low dose folic acid was found to be aneffective augmenting strategy in female patients with an inadequateresponse to fluoxetine therapy, and a longer term study of folic acidsupplementation in patients with both unipolar and bipolar depressionshowed statistically significant improvements in depressionsymptomatology. Strikingly, a recent study has demonstrated the efficacyof folic acid at higher dosages in the management of the manic phase ofbipolar disorder, indicating possible efficacy as a mood stabilizer.Methyl folate has been helpful as primary treatment in patientssuffering from comorbid depression and alcoholism. The related compoundfolinic acid (LEUCOVORIN®), a prescription drug utilized as an adjunctto chemotherapy agents, also showed a significant reduction indepression scores in patients who were inadequately responsive tomonotherapy with a serotonin reuptake inhibitor.

Folic acid is well tolerated even at high dosages. The presentdisclosure contemplates effective amounts of folic acid or a saltthereof to be in a range of about 0.5 mg to about 5 mg, inclusive, perday for a human subject, e.g., about 0.5 mg, about 1 mg, about 1.5 mg,about 2 mg, about 2.5 mg or about 3 mg, per day. In certain embodiments,folic acid or a salt thereof is provided in a range of between about 1mg to about 5 mg, between about 1 mg to about 4 mg, between 1 mg toabout 3 mg, or between about 1 mg to about 2 mg, inclusive. In certainembodiments, folic acid or a salt thereof is provided in a range ofbetween about 1 mg to about 3 mg.

A concern has been raised that extremely high doses of folic acid may beassociated with a slightly higher risk of colorectal polyps or tumors,but this is controversial. There is also a concern that high doses offolic acid increases prostate cancer risk (Figueiredo et al., J.National Cancer Institute (2009) 101:432-435 Additionally, the use offolic acid without monitoring of serum B₁₂ levels may mask occult B₁₂deficiency, which can be associated with irreversible neuro-cognitivechanges.

In certain embodiments, methyl folate, also known as Me-THF,N5-Methyl-THF, MTHF, 5-MTHF, L-methylfolate, and Levomefolic acid, or asalt thereof is substituted for folic acid in the therapeuticcombination, for example, as a way of enhancing efficacy and decreasingpotential risks and complications (such as the theoretical tumor riskfrom the administration of the parent folic acid). Methyl folate calciumsalt is available by prescription in the United States as Deplin®(L-methylfolate calcium salt). Methyl folate is also available as amedical food in the 7.5 mg to 45 mg dosage range. Methyl folate calciumsalt is also available outside of the United States as Metafolin®,Bodyfolin®, and Nutrifolin®.

Moreover, an subject with an abnormal folate metabolism may benefit fromthe contemplated combination therapy. For example, individuals with5-methyl tetrahydrofolate polymorphism, e.g., such as a C-to-Tsubstitution at nucleotide 677 (677→T) mutation of themethylenetetrahydrofolate reductase (MTHFR) gene (“MTHFR 677C 4 Tmutation”) (See, e.g., Antoniades et al., Circulation (2009)119:2507-2515), or an A-to-G substitution at nucleotide 2756 (2756A→G)mutation (See, e.g., Galbiatti et al., Braz. J. Med. Biol. Res. (2010)43:445-450), may benefit from the administration of methyl folate orfolinic acid rather than folic acid.

Effective amounts of methyl folate or a salt thereof range from about 1mg to about 45 mg per day for a human subject. In certain embodiments,about 5 mg to about 45 mg of methyl folate or a salt thereof per day isuseful, e.g., about 5 mg, about 7 mg, about 7.5 mg, about 10 mg, about15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,or about 45 mg, per day. In certain embodiments, methyl folate or a saltthereof is provided in a range of between about 5 mg to about 45 mg,between about 5 mg to about 40 mg, between 5 mg to about 35 mg, betweenabout 5 mg to about 30 mg, between about 5 mg to about 25 mg, betweenabout 5 mg to about 20 mg, between about 5 mg to about 15 mg, betweenabout 5 mg to about 10 mg, or between about 7 to about 15 mg, inclusive.In certain embodiments, methyl folate or a salt thereof is provided in arange of between about 5 mg to about 20 mg.

In certain embodiments, folinic acid or a salt thereof, such asLEUCOVORIN®, may be substituted for folic acid in the treatment.Effective amounts of folinic acid or a salt thereof range from about 5mg to about 15 mg per day for a human subject. In certain embodiments,about 5 mg to about 15 mg of methyl folate or a salt thereof per day isuseful, e.g., about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, orabout 15 mg, per day. In certain embodiments, methyl folate or a saltthereof is provided in a range of between about 5 mg to about 15 mg,between about 5 mg to about 10 mg, between 5 mg to about 9 mg, betweenabout 5 mg to about 8 mg, between about 5 mg to about 7 mg, or betweenabout 5 mg to about 6 mg, inclusive.

Compounds of Formula (I)

Compounds of Formula (I) have the general structure:

or a salt thereof,wherein:

R is hydrogen or —C(═O)R^(A), wherein R^(A) is unsubstituted C₁₀₋₁₈alkyl; and

R^(B) is of the formula:

wherein wherein m is 1, 2, 3, 4, 5, 6, or 7; and n is 1, 2, 3, 4, 5, 6,7, or 8.

As used herein, “alkyl” refers to a radical of a straight-chain orbranched saturated hydrocarbon group having from 10 to 18 carbon atoms(“C₁₀₋₁₈ alkyl”). In some embodiments, an alkyl group has 10 to 17carbon atoms (“C₁₀₋₁₇ alkyl”). In some embodiments, an alkyl group has10 to 16 carbon atoms (“C₁₀₋₁₆ alkyl”). In some embodiments, an alkylgroup has 10 to 15 carbon atoms (“C₁₀₋₁₅ alkyl”). In some embodiments,an alkyl group has 11 to 15 carbon atoms (“C₁₁₋₁₅ alkyl”). In someembodiments, an alkyl group has 12 to 15 carbon atoms (“C₁₂₋₁₅ alkyl”).In some embodiments, an alkyl group has 13 to 15 carbon atoms (“C₁₃₋₁₅alkyl”). In some embodiments, an alkyl group has 14 to 15 carbon atoms(“C₁₄₋₁₅ alkyl”). In some embodiments, an alkyl group has 15 to 18carbon atoms (“C₁₅₋₁₈ alkyl”). In some embodiments, an alkyl group has13 carbon atoms (“C₁₃ alkyl”), 14 carbon atoms (“C₁₄ alkyl”), 15 carbonatoms (“C₁₅ alkyl”), or 16 carbon atoms (“C₁₆ alkyl”).

In certain embodiments, the alkyl group is an n-alkyl group.

In certain embodiments, R is hydrogen. In certain embodiments, R is—C(═O)R^(A).

In certain embodiments, R^(A) is unsubstituted C₁₅₋₁₈ alkyl. In certainembodiments, R^(A) is unsubstituted C₁₅ n-alkyl, i.e., R is

In certain embodiments, —C(═O)R^(B) is an omega-3 fatty acid acyl moietyas provided in Table 1.

TABLE 1 Common name of omega-3 fatty acid Structure of —C(═)R^(B)α-Linolenic acid (ALA)

Eicosapentaenoic acid (EPA)

Docosapentaenoic acid (DPA), Clupanodonic acid

Docosahexaenoic acid (DHA)

In certain embodiments, —C(═O)R^(B) is of the formula:

In certain embodiments, —C(═O)R^(B) is of the formula:

In certain embodiments, the compound of Formula (I) is of the formula:

or a salt thereof, which is one of the active ingredients of Vayarin®.

In certain embodiments, the compound of Formula (I) is of the formula:

or a salt thereof, which is one of the active ingredients of Vayacog®.

In certain embodiments, the compound of Formula (I), or salt thereof, isprovided in the composition in a range of about 50 mg to about 1000 mg,inclusive; e.g., about 100 mg to about 500 mg, inclusive; about 100 mgto about 600 mg, inclusive; about 100 mg to about 700 mg, inclusive;about 100 mg to about 800 mg, inclusive; about 100 mg to about 900 mg,inclusive; about 50 mg to about 500 mg, inclusive; about 50 mg to about400 mg, inclusive; about 50 mg to about 300 mg, inclusive; about 50 mgto about 200 mg, inclusive; or about 50 mg to about 100 mg, inclusive.In certain embodiments, the compound of Formula (I), or salt thereof, isprovided in the composition in about 50 mg, 100 mg, 120 mg, 130 mg, 140mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg.

Omega-3 Fatty Acids or Salts Thereof

Omega-3 fatty acids, or salts thereof, which may sometimes be referredto as n-3 fatty acids or ω-3 fatty acids, are a family of unsaturatedfatty acids that have in common a final carbon-carbon double bond in then-3 position; that is, the third bond from the methyl end of the fattyacid.

Omega-3 fatty acids or salts thereof include a-linolenic acid (18:3,n-3; ALA), eicosapentaenoic acid (20:5, n-3; EPA), and docosahexaenoicacid (22:6, n-3; DHA). These three polyunsaturates have either 3, 5 or 6cis-double bonds in a carbon chain of 18, 20 or 22 carbon atoms,respectively. The human body cannot synthesize omega-3 fatty acids orsalts thereof de novo, but it can form 20-carbon unsaturated omega-3fatty acids or salts thereof (like EPA) and 22-carbon unsaturatedomega-3 fatty acids or salts thereof (like DHA) from the eighteen-carbonomega-3 fatty acid α-linolenic acid. These conversions occurcompetitively with n-6 fatty acids, which are essential closely relatedchemical analogues that are derived from linoleic acid. Both the omega-3α-linolenic acid and n-6 linoleic acid are essential nutrients whichmust be obtained from food sources.

Although omega-3 fatty acids or salts thereof have been known asessential to normal growth and health since the 1930s, awareness oftheir health benefits has dramatically increased in the past few years.New versions of ethyl esterized omega-3 fatty acids or salts thereof,such as E-EPA and combinations of E-EPA and E-DHA, have drawn attentionas highly purified and more effective products than the traditionalones. In the United States, these novel versions are often sold asprescription medications, such as LOVAZA®. In the European Union, theyare available as dietary supplements.

The health benefits of the long-chain omega-3 fatty acids or saltsthereof, DHA and EPA omega-3, are the best known. These benefits werediscovered in the 1970s by researchers studying the Greenland Inuittribe. The Greenland Inuit people consume large amounts of fat fromseafood but display virtually no cardiovascular disease. The high levelof omega-3 fatty acids or salts thereof consumed by this population canreduce triglycerides, heart rate, blood pressure, and atherosclerosis.

Most naturally-produced fatty acids (created or transformed in animal orplant cells with an even number of carbon in chains) are incis-configuration where they are more easily transformable. Thetrans-configuration results in much more stable chains that are verydifficult to further breakdown or transform, forming longer chains thataggregate in tissues and lacking the necessary hydrophilic properties.This trans-configuration can be the result of the transformation inalkaline solutions or of the action of some bacteria that shorten thecarbon chain. Natural transformations in plant or animal cells morerarely affect the last n-3 group itself. However, omega-3 compounds arestill more fragile than n-6 because the last double bond isgeometrically and electrically more exposed, notably in the natural cisconfiguration.

Table 2 provides different names for the most common omega-3 fatty acidsor salts thereof found in nature.

TABLE 2 Common name Lipid name Chemical name n/a 16:3 (n-3)all-cis-7,10,13-hexadecatrienoic acid α-Linolenic acid (ALA) 18:3 (n-3)all-cis-9,12,15-octadecatrienoic acid Stearidonic acid (SDA) 18:4 (n-3)all-cis-6,9,12,15-octadecatetraenoic acid Eicosatrienoic acid (ETE) 20:3(n-3) all-cis-11,14,17-eicosatrienoic acid Eicosatetraenoic acid (ETA)20:4 (n-3) all-cis-8,11,14,17-eicosatetraenoic acid Eicosapentaenoicacid (EPA) 20:5 (n-3) all-cis-5,8,11,14,17-eicosapentaenoic acidDocosapentaenoic acid (DPA), 22:5 (n-3)all-cis-7,10,13,16,19-docosapentaenoic acid Clupanodonic acidDocosahexaenoic acid (DHA) 22:6 (n-3)all-cis-4,7,10,13,16,19-docosahexaenoic acid Tetracosapentaenoic acid24:5 (n-3) all-cis-9,12,15,18,21-docosahexaenoic acid Tetracosahexaenoicacid 24:6 (n-3) all-cis-6,9,12,15,18,21-tetracosenoic acid (nisinicacid)

Omega-3 fatty acids, or salts thereof, have been suggested to havemembrane-enhancing capabilities in brain cells. One medical explanationis that omega-3 fatty acids, or salts thereof, play a role in thefortification of the myelin sheaths around neurons.

A benefit of omega-3 fatty acids, or salts thereof, is believed to be,inter alia, helping the brain to repair damage by promoting neuronalgrowth. In a six-month study involving people with schizophrenia andHuntington's disease who were treated with E-EPA or a placebo, theplacebo group had clearly lost cerebral tissue, while the patients giventhe supplements had a significant increase of grey and white matter.

In the prefrontal cortex (PFC) of the brain, low brain omega-3 fattyacids, or salts thereof, are thought to lower the dopaminergicneurotransmission in this brain area, possibly contributing to thenegative and neurocognitive symptoms in schizophrenia. This reduction indopamine system function in the PFC may lead to an overactivity indopaminergic function in the limbic system of the brain which issuppressively controlled by the PFC dopamine system, causing thepositive symptoms of schizophrenia. This is called the omega-3polyunsaturated fatty acid/dopamine hypothesis of schizophrenia. Thismechanism may explain why omega-3 supplementation shows effects againstboth positive, negative, and neurocognitive symptoms in schizophrenia.

Consequently, the past decade of omega-3 fatty acid research has led tosome Western interest in omega-3 fatty acids, or salts thereof, as beinga legitimate “brain food.” A significant focus of research, however,lies in the role of omega-3 fatty acids, or salts thereof, as anon-prescription treatment for certain psychiatric and mental diagnosesand has become a topic of much research and speculation.

In a 1998, a small double-blind placebo-controlled study in thirtypatients diagnosed with bipolar disorder was conducted. Most subjects inthis study were already undergoing psychopharmacological treatment(e.g., 12 out of the 30 were taking lithium). Over the course of fourmonths, 15 subjects were given capsules containing olive oil, andanother 15 subjects were given capsules containing nine grams ofpharmaceutical-quality EPA and DHA. The study showed that subjects inthe omega-3 group were less likely to experience a relapse of symptomsin the four months of the study. Moreover, the omega-3 group experiencedsignificantly more recovery than the placebo group.

Although the sample size of the study was too small to be clinicallysignificant, additional lines of evidence subsequently emerged whichappear to support the notion that omega-3 fatty acids, or salts thereof,may have beneficial effects on the psychiatric health of patients. Forexample, several epidemiological studies suggest co-variation betweenseafood consumption and rates of mood disorders. Biological markerstudies indicate deficits in omega-3 fatty acids, or salts thereof, inpeople with depressive disorders, while several treatment studiesindicate therapeutic benefits from omega-3 supplementation. A similarcontribution of omega-3 fatty acids, or salts thereof, to the preventionof coronary artery disease may explain the well-described links betweencoronary artery disease and depression. Deficits in omega-3 fatty acidsor salts thereof have been identified as a contributing factor to mooddisorders and offer a potential rational treatment approach.Furthermore, a study conducted in 2004 found that 100 suicide attemptpatients on average had significantly lower levels of EPA in their bloodas compared to controls (Huan et al., Biological psychiatry (2004) 56:490-6).

Based on these lines of evidence, in 2006 the Omega-3 fatty acids, orsalts thereof, Subcommittee, assembled by the Committee on Research onPsychiatric Treatments of the American Psychiatric Association (APA)stated that the preponderance of epidemiologic and tissue compositionalstudies supports a protective effect of omega-3 fatty acid intake,particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),in mood disorders. Meta-analyses of randomized controlled trialsdemonstrate a statistically significant benefit in unipolar and bipolardepression (p=0.02). The results were highly heterogeneous, indicatingthat it is important to examine the characteristics of each individualstudy to note the differences in design and execution. EPA and DHAappear to have negligible risks and some potential benefit in majordepressive disorder and bipolar disorder, but results remaininconclusive in most areas of interest in psychiatry. Health benefits ofomega-3 EPA may be especially important in patients withneuropsychiatric conditions due to high prevalence rates of smoking andobesity and the metabolic side effects of some psychotropic medications.

Another meta-analysis published in the Journal of Clinical Psychiatry in2007, based on 10 clinical trials, found that omega-3 polyunsaturatedfatty acids significantly improved depression in patients with bothunipolar and bipolar disorder. However, based upon the heterogeneity ofthe trials, the authors concluded that more large-scale, well-controlledtrials were needed to find out the favorable target subjects,therapeutic dose of EPA and the composition of omega-3 PUFAs in treatingdepression. Additionally, a small American trial, published in 2009,suggests that E-EPA, as monotherapy, has an advantage over placebo inmajor depressive disorder (Mischoulon et al., J Clin Psychiatry. 200970:1636-1644). Conversely, a recent trial of DHA in a mood-disorderedpopulation had a negative result.

Omega-3 fatty acids, or salts thereof, in the form of fish oils areincreasingly popular nutritional supplements which have shown efficacyas adjunctive therapy in the management of bipolar disorder, as well asin some studies of unipolar depressive illness. The mechanism of theomega-3 fatty acids, or salts thereof, in this population may involve ageneral neuroprotective effect, as well as possibly increasedserotonergic or dopaminergic neurotransmission.

Thus, the methods and compositions described herein comprise one or moreomega-3 fatty acids, or salts thereof, as part of a novel combination oftherapeutics which acts synergistically and/or additively to treat avariety of conditions, such as a neuropsychiatric condition, e.g.,depression.

It is further contemplated that about 500 mg to 5 grams of the one ormore omega-3 fatty acids, or salts thereof, per day for a subject issuitable; e.g., about 500 mg, about 600 mg, about 700 mg, about 800 mg,about 900 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600mg, about 1800 mg, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about4 g, about 4.5 g, or about 5 g, per day. In certain embodiments, one ormore omega-3 fatty acids or salts thereof is provided in a range ofbetween about 500 mg to about 5 g, between about 500 mg to about 4 g,between 500 mg to about 3 g, between about 500 mg to about 2 g, betweenabout 500 mg to about 1900 mg, between about 500 mg to about 1800 mg,between about 500 mg to about 1700 mg, between about 500 mg to about1600 mg, between about 500 mg to about 1500 mg, between about 500 mg toabout 1400 mg, between about 500 mg to about 1300 mg, between about 500mg to about 1200 mg, between about 500 mg to about 1100 mg, betweenabout 500 mg to about 1000 mg, between about 500 mg to about 900 mg, orbetween about 800 mg to about 1600 mg, inclusive. In certainembodiments, one or more omega-3 fatty acids, or salts thereof, isprovided in a range of between about 800 mg to about 1600 mg.

In some embodiments, omega-3 fatty acids, or salts thereof, useful inthe therapeutic combination are selected from E-EPA, EPA, DHA, orcombinations thereof. In some embodiments, a higher proportion of EPA toother omega-3 fatty acids, or salts thereof, is used. For example, incertain embodiments, the one or more omega-3 fatty acids, or saltsthereof, is rich in EPA or E-EPA, i.e., comprising at least about 50%EPA or E-EPA. In certain embodiments, the one or more omega-3 fattyacids, or salts thereof, comprise at least about 55%, at least about60%, at least about 65%, at least about 70%, at least about 80%, atleast about 90%, at least about 95%, of the one or more omega-3 fattyacids, or salts thereof, is EPA or E-EPA. In certain embodiments, theone or more omega-3 fatty acids, or salts thereof, is 100% EPA or E-EPA.In certain embodiments, the one or more omega-3 fatty acids, or saltsthereof, comprise between about 50% to about 100% EPA or E-EPA, betweenabout 55% to about 100% EPA or E-EPA, between about 60% to about 100%EPA or E-EPA, between about 65% to about 100% EPA or E-EPA, betweenabout 70% to about 100% EPA or E-EPA, between about 75% to about 100%EPA or E-EPA, between about 80% to about 100% EPA or E-EPA, betweenabout 85% to about 100% EPA or E-EPA, between about 90% to about 100%EPA or E-EPA, or between about 95% to about 100% EPA or E-EPA.

Omega-3 fatty acids, or salts thereof, are generally well tolerated, butthey may result in mild gastrointestinal disturbances and fish taste inthe subject's mouth. The supplements are believed to be non-toxic. Thepreponderance of formulations with different proportions of the primaryomega-3 fatty acids, or salts thereof, EPA and DHA, as well as a concernabout concentrated forms of the supplements possibly containing mercuryfrom high fat fish such as tuna, are potential complications in usingthese substances in a large patient population.

Vitamins D3 and B₁₂

Vitamin D3, also known as cholecalciferol, is contemplated as anoptional components of the therapeutic combination. In certainembodiments, vitamin D3 is provided in the composition in a range ofbetween about 500 International Units (IU) to about 2000 InternationalUnits (IU), inclusive, e.g., between about 800 IU to about 1500 IU,inclusive; between about 500 IU to about 1200 IU, inclusive; betweenabout 800 IU to about 1200 IU, inclusive; about 500 IU, 600 IU, 700 IU,800 IU, 900 IU, 1000 IU, 1100 IU, 1200 IU, 1300 IU, 1400 IU, 1500 IU,1600 IU, 1700 IU, 1800 IU, 1900 IU, or 2000 IU. In certain embodiments,vitamin D3 is provided in the composition in about 1000 IU.

Vitamin B₁₂, also called cobalamin, is also contemplated as an optionalcomponent of the therapeutic combination. Vitamin B₁₂ is a water solublevitamin (formula: C₆₃H₈₈CoN₁₄O₁₄P) with a key role in the normalfunctioning of the brain and nervous system, and for the formation ofblood. In certain embodiments, amounts of vitamin B₁₂ effective fortreating a human subject with a neuropsychiatric condition, such asdepression, is in a range of about 100 μg to about 2000 μg per day,e.g., about 100 μg, about 200 μg, about 300 μg, about 400 μg, about 500μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1000μg, about 1500 μg, or about 2000 μg, per day. In certain embodiments,vitamin B₁₂ is provided in a range of between about 100 μg to about 2000μg, between about 100 μg to about 1000 μg, between about 200 μg to about1500 μg, between about 500 μg to about 1500 μg, between about 500 μg, toabout 1000 μg, or between about 50 μg to about 500 μg, per day. Incertain embodiments, vitamin B₁₂ is provided in a range of between about50 μg to 500 μg, per day.

St. John's Wort

Additionally, St. John's Wort (Hypericum perforatum) has beenextensively studied in treating depression, and while it appears to haveefficacy in mild to moderate depressive illness in a number ofcontrolled studies, conflicting results from meta-analyses have limitedthe willingness of physicians and other practitioners to prescribe thissubstance. A second consideration is that the substance is an herbalextract with multiple chemical constituents, some of which may interferewith the metabolism of prescribed medications.

St. John's Wort carries certain intrinsic limitations with respect toboth the lack of robust evidence of efficacy in meta-analyses and itspossible metabolic interactions with prescription drugs. In someembodiments described herein, the method and/or composition may furthercomprise St. John's Wort. In other embodiments, St. John's Wort isexcluded in the methods and compositions contemplated herein.

Neuropsychiatric Conditions

As generally described above, the methods and compositions describedherein are broadly effective for the treatment of neuropsychiatricconditions. Exemplary neuropsychiatric conditions that may be treatedwith the methods, compositions, and therapies include, but are notlimited to, mood disorders or conditions characterized by atypical mood.A mood disorder is the term given for a group of diagnoses in theDiagnostic and Statistical Manual of Mental Disorders (DSM IV TR)classification system where a disturbance in the subject's mood ishypothesized to be the main underlying feature. The classification isknown as mood (affective) disorders in ICD 10. Exemplary mood disordersinclude, but are not limited to depression (e.g., Major DepressiveDisorder), Bipolar Disorder, and Anxiety Disorder. Exemplary conditionscharacterized by atypical mood (e.g., depressed mood, irritability,instability of mood, and/or changes in mood), include, but are notlimited to, stress, hormonal mood swings (e.g., during pregnancy,post-partum, Premnstrual Dysphoric Disorder and related conditions,puberty, and menopause), Mild Cognitive Impairment, substance-inducedmood disorders (e.g., alcoholism), dementia, Alzheimer's disease,Parkinson's disease, Huntington's disease, and psychotic disorders(e.g., Schizoaffective Disorder, Schizophrenia, Delusional Disorder, andPsychotic Disorder Not Otherwise Specified).

In certain embodiments, the neuropsychiatric condition is a conditioncharacterized by atypical mood. In certain embodiments, theneuropsychiatric condition is selected from stress, hormonal moodswings, Mild Cognitive Impairment, substance-induced mood disorders,dementia, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, and psychotic disorders.

In certain embodiments, the neuropsychiatric condition is hormonal moodswings, and the mood swings take place during pregnancy, post-partum,during puberty, or during menopause, or are a result of a PremenstrualDysphoric Disorder or related condition. In certain embodiments, thesubject is a post-partum subject.

In certain embodiments, the neuropsychiatric condition issubstance-induced mood disorder, and the mood disorder is induced byalcohol (e.g., alcoholism).

In certain embodiments, the neuropsychiatric condition is a psychoticdisorder selected from the group consisting of Schizoaffective Disorder,Schizophrenia, Delusional Disorder, and Psychotic Disorder Not OtherwiseSpecified.

In certain embodiments, the neuropsychiatric condition is a mooddisorder. In certain embodiments, the mood disorder is Bipolar Disorder(e.g., the subject is a human subject who has been diagnosed with aBipolar Disorder). In certain embodiments, the Bipolar Disorder is adepressed or mixed phase of Bipolar Disorder. In other embodiments, thesubject is a human subject who is not diagnosed with a Bipolar Disorder.In some embodiments, the subject is a human subject who has notexhibited an episode of mania (“manic episode”).

In certain embodiments, the mood disorder is anxiety (e.g., the subjectis a human subject who has an Anxiety Disorder).

In certain embodiments, the mood disorder is depression. In certainembodiments, the depression is a Major Depressive Disorder (MDD). Incertain embodiments, the depression is dysthymia (dysthymic disorder).

A major depressive episode is characterized by the presence of aseverely depressed mood that generally persists for at least two weeks.Episodes may be isolated or recurrent and are categorized as mild (fewsymptoms in excess of minimum criteria), moderate, or severe (markedimpact on social or occupational functioning). An episode with psychoticfeatures, commonly referred to as psychotic depression, is automaticallyrated as severe. If the patient has had an episode of mania or markedlyelevated mood, a diagnosis of bipolar disorder is made instead.Depression without mania is sometimes referred to as unipolar becausethe mood remains at one emotional state or “pole.”

The most widely used criteria for diagnosing depressive conditions arefound in the American Psychiatric Association's revised fourth editionof the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV-TR), and the World Health Organization's InternationalStatistical Classification of Diseases and Related Health Problems(ICD-10) which uses the name recurrent depressive disorder. The lattersystem is typically used in European countries, while the former is usedin the United States and many other non-European nations, and theauthors of both have worked towards conforming one with the other.

Major depressive disorder is classified as a mood disorder in DSM-IV-TR.The diagnosis hinges on the presence of a single or recurrent majordepressive episode. Further qualifiers are used to classify both theepisode itself and the course of the disorder. The category depressivedisorder not otherwise specified is diagnosed if the depressiveepisode's manifestation does not meet the criteria for a majordepressive episode. The ICD-10 system does not use the term majordepressive disorder, but lists very similar criteria for the diagnosisof a depressive episode (mild, moderate, or severe); the term recurrentmay be added if there have been multiple episodes without mania.

The DSM-IV-TR recognizes five further subtypes of MDD, calledspecifiers, in addition to noting the length, severity, and presence ofpsychotic features:

-   -   (1) Melancholic depression is characterized by a loss of        pleasure in most or all activities, a failure of reactivity to        pleasurable stimuli, a quality of depressed mood more pronounced        than that of grief or loss, a worsening of symptoms in the        morning hours, early morning waking, psychomotor retardation,        excessive weight loss (not to be confused with anorexia        nervosa), or excessive guilt.    -   (2) Atypical depression is characterized by mood reactivity        (paradoxical anhedonia) and positivity, significant weight gain        or increased appetite (comfort eating), excessive sleep or        sleepiness (hypersomnia), a sensation of heaviness in limbs        known as leaden paralysis, and significant social impairment as        a consequence of hypersensitivity to perceived interpersonal        rejection.    -   (3) Catatonic depression is a rare and severe form of major        depression involving disturbances of motor behavior and other        symptoms. Here the person is mute and almost stuporose, and        either remains immobile or exhibits purposeless or even bizarre        movements. Catatonic symptoms also occur in schizophrenia or in        manic episodes, or may be caused by neuroleptic malignant        syndrome.    -   (4) Postpartum depression (mild mental and behavioral disorders        associated with the puerperium, not elsewhere classified in        ICD-10) refers to the intense, sustained and sometimes disabling        depression experienced by women after giving birth. Postpartum        depression, which has incidence rate of 10-15% among new        mothers, typically sets in within three months of labor, and        lasts as long as three months.    -   (5) Seasonal affective disorder (SAD) is a form of depression in        which depressive episodes come on in the autumn or winter, and        resolve in spring. The diagnosis is made if at least two        episodes have occurred in colder months with none at other        times, over a two-year period or longer.

To confer major depressive disorder as the most likely diagnosis, otherpotential diagnoses must be considered, including dysthymia, adjustmentdisorder with depressed mood, and bipolar disorder. Dysthymia is achronic, milder mood disturbance in which a person reports a low moodalmost daily over a span of at least two years. The symptoms are not assevere as those for major depression, although people with dysthymia arevulnerable to secondary episodes of major depression (sometimes referredto as double depression). Adjustment disorder with depressed mood is amood disturbance appearing as a psychological response to anidentifiable event or stressor, in which the resulting emotional orbehavioral symptoms are significant but do not meet the criteria for amajor depressive episode. Bipolar disorder, previously known asmanic-depressive disorder, is a condition in which depressive phasesalternate with periods of mania or hypomania. Although depression iscurrently categorized as a separate disorder, there is ongoing debatebecause individuals diagnosed with major depression often experiencesome hypomanic symptoms, indicating a mood disorder continuum.

The criteria have been criticized because they do not take into accountany other aspects of the personal and social context in which depressioncan occur. In addition, some studies have found little empirical supportfor the DSM-IV cut-off criteria, indicating they are a diagnosticconvention imposed on a continuum of depressive symptoms of varyingseverity and duration: excluded are a range of related diagnoses,including dysthymia which involves a chronic but milder mooddisturbance, recurrent brief depression which involves brieferdepressive episodes, minor depressive disorder which involves only someof the symptoms of major depression, and adjustment disorder withdepressed mood which involves low mood resulting from a psychologicalresponse to an identifiable event or stressor.

There are significant practical implications for the diagnosis ormisdiagnosis of MDD versus other related but distinct disorders inregards to prescription anti-depressant-based therapies because theseconditions are generally treated with different sets of medications. Forexample, widely used anti-depressants such as SSRIs, which areprescribed to patients diagnosed with MDD, may cause adverse effectswith potentially severe clinical consequences, or, conversely, may showlack of efficacy when unknowingly prescribed to patients with bipolardisorder, which is, unfortunately, a fairly common clinical scenario. Bycontrast, these risks can be circumvented by using the compositions andmethods described herein. The therapy contemplated provides a safe andeffective alternative for treating conditions that broadly include mooddisorders, ranging from mild mood disturbances such as dysthymia tosevere forms of depression such as MDD. Therefore, for those manifestingcertain symptoms of a mood disorder but where diagnosis of MDD is as yetambiguous and therefore may not meet the clinical criteria appropriatefor treatment with a prescription anti-depressant-based drug therapy,the therapy can still be safely administered.

Symptoms of Depression

Subjects who may benefit from the therapy described herein can beidentified by practitioners using routine evaluations. The challengefacing clinicians striving for an accurate diagnosis of these conditionsstems in part from the fact that there are a number of overlappingsymptoms across these conditions. Many of these symptoms, which aredescribed in more detail below, can be remedied or alleviated when thetherapy is used according to this disclosure.

A person suffering a major depressive episode usually exhibits a verylow mood, which pervades all aspects of life, and an inability toexperience pleasure in activities that formerly were enjoyed. Depressedpeople may be preoccupied with, or ruminate over, thoughts and feelingsof worthlessness, inappropriate guilt or regret, helplessness,hopelessness, and self-hatred. In severe cases, depressed people mayhave symptoms of psychosis. These symptoms include delusions or, lesscommonly, hallucinations, usually of an unpleasant nature. Othersymptoms of depression include poor concentration and memory (especiallyin those with melancholic or psychotic features), withdrawal from socialsituations and activities, reduced sex drive, and thoughts of death orsuicide.

Insomnia is common in the depressed population. In the typical pattern,a person wakes very early and is unable to get back to sleep.Hypersomnia, or oversleeping, is less common. Appetite often decreases,with resulting weight loss, although increased appetite and weight gainoccasionally occur. The person may report multiple physical symptomssuch as fatigue, headaches, or digestive problems; physical complaintsare the most common presenting problem in developing countries,according to the World Health Organization's criteria for depression.Family and friends may notice that the person's behavior is eitheragitated or lethargic.

Depressed children often display an irritable rather than a depressedmood, and show varying symptoms depending on age and situation. Mostexhibit a loss of interest in school and a decline in academicperformance. They may be described as clingy, demanding, dependent, orinsecure. Diagnosis may be delayed or missed when symptoms areinterpreted as normal moodiness. Depression may also coincide withattention-deficit hyperactivity disorder (ADHD), complicating thediagnosis and treatment of both.

High risks associated with misdiagnosis and misuse of a prescriptionanti-depressant are markedly reduced for the therapy. For instance, fora population of subjects who may be categorized near “borderline” forthe diagnosis of MDD and therefore may not receive a prescriptionanti-depressant due to inherent risks may still be safely administered atherapy described herein.

Diagnosis and Clinical Assessment

Generally, a diagnostic assessment requires that it be conducted by ageneral practitioner, or by a psychiatrist or psychologist, who recordsthe person's current circumstances, biographical history, and currentsymptoms, and a family medical history to see if other family membershave suffered from a mood disorder, and discusses the person's alcoholand drug use. The assessment also includes a mental state examination,which is an assessment of the person's current mood and thought content,in particular the presence of themes of hopelessness or pessimism,self-harm or suicide, and an absence of positive thoughts or plans.Specialist mental health services are rare in rural areas, and thusdiagnosis and management is largely left to primary care clinicians.This issue is even more marked in developing countries. The score on arating scale alone is not sufficient to diagnose depression, but itprovides an indication of the severity of symptoms for a time period, soa person who scores above a given cut-off point can be more thoroughlyevaluated for a depressive disorder diagnosis. Several rating scales areused for this purpose. Screening programs have been advocated to improvedetection of depression, but there is evidence that they do not improvedetection rates, treatment, or outcome.

Primary care physicians and other non-psychiatrist physicians havedifficulty diagnosing depression. In light of the fact thatnon-psychiatrists miss two-thirds of cases and unnecessarily treat otherpatients, these patients who fall within the “gray area” of diagnosis ofrelated psychiatric disorders may greatly benefit from the therapydescribed herein.

Before diagnosing a mood disorder, such as major depressive disorder, adoctor generally performs a medical examination and selectedinvestigations to rule out other causes of symptoms. These include bloodtests measuring TSH and thyroxine to exclude hypothyroidism; basicelectrolytes and serum calcium to rule out a metabolic disturbance; anda full blood count including ESR to rule out a systemic infection orchronic disease. Adverse affective reactions to medications or alcoholmisuse are often ruled out, as well. Testosterone levels may beevaluated to diagnose hypogonadism, associated with depression in men.The step of eliminating other potential causes such as these, which areusually traced to physical or mechanical bases, as opposed topsychiatric or biochemical, should be performed for accurate diagnosisof a mood disorder.

Subjective cognitive complaints appear in older depressed people, butthey can also be indicative of the onset of a dementing disorder, suchas Alzheimer's disease. Depression is also a common initial symptom ofdementia. The challenge includes the fact that no biological testsconfirm major depression. For prescribing a prescription anti-depressantsuch as an SSRI, therefore, cognitive testing and brain imaging aregenerally used to help distinguish depression from dementia. A CT scanor MRI exam may also be used to exclude brain pathology in those withpsychotic, rapid-onset or otherwise unusual symptoms before aprescription anti-depressant may be prescribed to the patient. Theprocess is time-consuming, expensive and accompanies risks ofmisdiagnosis and improper use of anti-depressant drugs. These problemsmay be greatly eliminated by using instead the compositions and methodsdescribed herein. The therapy described here is believed to be alsoeffective for treating depression that is associated with dementia. Itis understood by one of ordinary skill in the art that such therapy maybe administered in conjunction with additional therapeutic directed totreat the underlying pathology, such as dementia and/or Alzheimer'sdisease.

In some embodiments, similarly, the therapy is also useful for treatingmood disorders associated with or induced by substance abuse (e.g.,alcohol or drug consumption). Without being bound by any particulartheory, it is believed that the particular combinations of therapeuticsdescribed herein can synergistically act as a general mood stabilizer.As such, the combination of therapeutics contemplated herein can be usedto treat mood disturbances triggered by extrinsic and/or behavioralattributes such as substance abuse without the risks that prescriptionanti-depressants may pose.

Surprisingly, the combination of therapeutics described herein may alsobe effective as a mood-stabilizer or anxiolytic. Therefore, thetreatment protocol and/or composition may also be useful for thetreatment of the depressed or mixed phase of bipolar disorders, anxietydisorders, and related conditions such as atypical mood disorders, inwhich subjects would benefit from stabilizing or neutralizing moods.This may be particularly useful for subjects who experience or arelikely to experience adverse side effects from prescriptionanti-depressant therapies, which are known to cause certain degree ofirritability in patients. Some of these side effects associated withprescription anti-depressants are described in more detail herein.

Thus, the therapy does not present many of the issues and risksassociated with prescription anti-depressant-based therapies (e.g.,delayed or inaccurate diagnosis, misdiagnosis, misuse ofanti-depressants, inherent risks associated with the drugs that requirecaution, significant side effects which may lead to noncompliance,especially sexual side effects, and possibly emergent suicidalityassociated with anti-depressant treatment of pediatric populations) andtherefore can be used more liberally and safely, and as effectively, ascompared to a typical SSRI-based therapy for treating a broad spectrumof mood disorders. Again, the therapy causes little, if any, sideeffects and adverse drug interactions even when used together with othertherapeutics.

Thus, in any of the above embodiments, the method may further comprisethe step of identifying a subject having or at risk of developing a MDD.

In any of the above embodiments, the method of treatment may furthercomprise the step of monitoring the effectiveness of the treatment inthe subject over a period of time.

Prescription Anti-Depressant Therapies and Side Effects

As mentioned, the therapy offers much advantage over prescriptionanti-depressants and may be substituted partially or entirely for thetreatment of a neuropsychiatric condition, such as depression.

However, it may be useful to also administer together or separately aprescription anti-depressant with the therapy. Various types (e.g.,classes) of anti-depressants are known and commercially available andare in some cases referred to as “conventional” anti-depressants. Anysubjects who take one or more of these anti-depressants may therefore begood candidates for receiving the therapy.

Thus, in some embodiments, the method involves a combination therapycomprising administering the therapy together with one or moreprescription anti-depressants. In certain embodiments, the prescriptionanti-depressant therapy is administered to the subject in an amount noteffective to treat the condition when administered alone.

Prescription anti-depressants include, but are not limited to: selectiveserotonin reuptake inhibitors (SSRIs), serotonin and dopamine reuptakeinhibitors (SDRIs), serotonin-norepinephrine reuptake inhibitors(SNRIs), serotonin-noradrenaline-dopamine reuptake inhibitors (SNDRIs),norepinephrine-dopamine reuptake inhibitors (NDRIs), norepinephrine(noradrenaline) reuptake inhibitors (NRIs), monoamine oxidase inhibitors(MAOIs), selective serotonin reuptake enhancers (SSREs), melatonergicagonists, tryptamines, tricyclic anti-depressants, and atypicalanti-depressants.

SSRIs are said to work by preventing the reuptake of serotonin (5-HT) bythe presynaptic neuron, thus maintaining higher levels of 5-HT in thesynapse. Examples of SSRIs include but are not limited to the following(trade names in parentheses): alaproclate; amoxapine; citalopram (suchas CELEXA®, CIPRAMIL®, EMOCAL®, SEPRAM® and SEROPRAM®); clomipramine;dapoxetine; duloxetine (such as CYMBALTA®); escitalopram oxalate (suchas LEXAPRO®, CIPRALEX® and ESERTIA®); femoxetine; fenfluramine;fluoxetine (such as PROZAC®, FONTEX®, SEROMEX®, SERONIL®, SARAFEM®,FLUCTIN® (EUR), and FLUOX® (NZ)); fluvoxamine maleate (such as LUVOX®,FAVERIN®, and DUMYROX®); indalpine; milnacipran; norfenfluramine;olanzapine; paroxetine (such as PAXIL®, SEROXAT®, AROPAX®, DEROXAT®,REXETIN®, XETANOR®, and PAROXAT®); sertraline (such as ZOLOFT®, LUSTRAL®and SERLAIN®); trazodone (such as DESYREL®, MOLIPAXIN®, TRITTICO®,THOMBRAN®, TRIALODINE®, TRAZOREL®, TRITICUM®, and TRAZONE®); venlafaxineand zimelidine.

Bupropion, sold as WELLBUTRIN®, is a non-limiting example of a serotoninand dopamine reuptake inhibitor (SDRI).

Non-limiting examples of SNRIs include: venlafaxine (EFFEXOR XR®,EFFEXOR®); desvenlafaxine (PRISTIQ®) available from Wyeth; sibutramine(MERIDIA®, REDUCTIL®); nefazodone (SERZONE®); milnacipran(DALCIPRAN®/Portugal; IXEL®/France); duloxetine (CYMBALTA®) availablefrom Eli Lilly and Company; and, bicifadine available from DOVPharmaceutical.

SNDRIs are the serotonin-noradrenaline-dopamine reuptake inhibitors.Non-limiting examples of SNDRIs include: tesofensine, brasofensine; andGlaxoSmithKline's NS2359; Nomifensine; Venlafaxine (EFFEXOR®) andSibutramine (MERIDIA®/REDUCTIL®).

Norepinephrine-dopamine reuptake inhibitors (NDRI) such as bupropion(WELLBUTRIN®, ZYBAN®) inhibit the neuronal reuptake of dopamine andnorepinephrine (noradrenaline).

Noradrenergic and specific serotonergic anti-depressants (NASSAs) form anewer class of anti-depressants which purportedly work to increasenorepinephrine (noradrenaline) and serotonin neurotransmission byblocking presynaptic alpha-2 adrenergic receptors while at the same timeminimizing serotonin related side-effects by blocking certain serotoninreceptors. The only example of this class in clinical use is mirtazapine(AVANZA®, ZISPIN®, REMERON®).

Norepinephrine (noradrenaline) reuptake inhibitors (NRIs) such asreboxetine (EDRONAX®) act via norepinephrine (also known asnoradrenaline). NRIs are thought to have a positive effect onconcentration and motivation in particular. These include, withoutlimitation, atomoxetine, maprotiline, nisoxetine, reboxetine, viloxazineand TCAs/Tetras (such as AMITRIPTYLINE®, AMOXAPINE®, BUTRIPTYLINE®,DESIPRAMINE®/LOFEPRAMINE®, DIBENZEPIN®, DOSULEPIN®, DOXEPIN®,IMIPRAMINE®, IPRINDOLE®, MELITRACEN®, NORTRIPTYLINE®, OPIPRAMOL®,PROTRIPTYLINE®, TRIMIPRAMINE®, and MAPROTILINE®).

Monoamine oxidase inhibitors (MAOIs) are a class of powerfulanti-depressant drugs that act by inhibiting the activity of monoamineoxidase preventing the breakdown of monoamine neurotransmitters, whichincreases their availability. There are two isoforms of monoamineoxidase, MAO-A and MAO-B. Non-limiting examples of MAOIs include:iproclozide, iproniazid, isocarboxazid, nialamide, pargyline,phenelzine, rasagiline, selegiline, toloxatone, tranylcypromine, RIMAs(brofaromine, beta-carbolines (harmaline) and moclobemide).

Selective serotonin reuptake enhancers (SSREs) are anti-depressants thatenhance the reuptake of serotonin instead of inhibiting it, as tricyclicanti-depressants and selective serotonin reuptake inhibitors (SSRIs) do.One known selective serotonin reuptake enhancer is tianeptine (INN)(available under the tradenames: STABLON®, COAXIL®, and TATINOL®).

Furthermore, tricyclic anti-depressants (TCAs) work on both serotoninand norepinephrine transporters. This class includes desipramine, whichis sold under the trade names of NORPRAMIN® and PERTOFRANEIS®.

Another class of anti-depressant more recently made available includes amelatonergic anti-depressant, such as VALDOXAN® (agomelatine).

Problems associated with these therapeutic regimen include adverse orunwanted side effects and lack of responsiveness in certainsub-population of affected individuals. Therefore, the therapeuticmethods and compositions described herein are particularly suitable forsubjects who either experience unwanted side effects from prescriptionanti-depressant therapies or at risk of developing adverse effects, aswell as those who do not benefit from the conventional approach.

For example, in some cases, a patient suffering from MDD is classifiedto be a “non-responder.” The term “non-responder” refers to a subjectwho is resistant to a particular therapy, e.g., agent or drug such as anSSRI-based therapy. Thus, in some cases, a non-responder patient isunresponsive or substantially unresponsive to SSRI treatment. As usedherein, “unresponsive or substantially unresponsive to SSRI treatment”means that the patient does not significantly improve symptoms and/orseverity of the disorder in response to the SSRI treatment. Evaluationof patients in assessing symptoms and/or severity of the disorder may becarried out by various methods, which are known in the art. Theevaluation may take into account numerous criteria, as determined bysuitable biochemical, physiological and/or behavioral factors.

Some patients experience adverse or undesired side effects from aconvention drug therapy. The most widely prescribed anti-depressantscome from a class of medications known as selective serotonin reuptakeinhibitors (SSRIs). Examples of SSRIs include, but are not limited to,fluoxetine (PROZAC®), fluvoxamine (LUVOX®), sertraline (ZOLOFT®),paroxetine (PAXIL®), escitalopram (LEXAPRO®), and citalopram (CELEXA®).The SSRIs act on serotonin in the brain. Serotonin plays a role in theregulation of mood, digestion, pain, sleep, mental clarity, and otherbiological functions. As a result, the SSRI anti-depressants can cause awide range of side effects. Some side effects of SSRI anti-depressantsinclude, but are not limited to, nausea, insomnia, anxiety,restlessness, decreased sex drive, dizziness, weight gain or loss,tremors, sweating, sleepiness, fatigue, dry mouth, diarrhea,constipation and headaches. Common side effects include sexual problemsincluding delayed orgasm or anorgasmia in both sexes, erectiledysfunction in men, drowsiness, sleep difficulties, and nausea. Whilesome side effects subside after the first few weeks of drug treatment,others persist and may even get worse. In pediatric and young adultpopulations up till the age of 24, the SSRIs have been associated withthe emergence of suicidal ideation and behavior. In addition, for olderpatients (e.g., 65 or older), SSRIs may pose an additional concern.Studies have shown that SSRI medications may increase the risk forfalls, fractures, and bone loss in older adults. The SSRIs can alsocause serious withdrawal symptoms when discontinued abruptly.

There are a variety of newer anti-depressant drugs, termed atypicalanti-depressants, which target other neurotransmitters either alone orin addition to serotonin. Some of the brain chemicals they affectinclude norepinephrine and dopamine.

The atypical anti-depressants include, but are not limited to: bupropion(WELLBUTRIN®), mirtazapine (REMERON®), venlafaxine (EFFEXOR®),duloxetine (CYMBALTA®), trazodone (DESYREL®), and nefazodone (formerlyavailable as SERZONE®). The side effects vary according to the specificdrug. However, many of the atypical anti-depressants can cause nausea,fatigue, weight gain, sleepiness, nervousness, dry mouth, and blurredvision.

Side effects of older anti-depressant drugs are generally more severethan those of the newer drugs. As such, they are usually only prescribedas a last resort after other treatments and medications have failed. Forexample, tricyclic anti-depressants and MAOIs (monoamine oxidaseinhibitors) are older classes of anti-depressants. People taking MAOIsneed to be careful about the foods they eat and the medicines they take.For example, the tricyclic drugs are cardiotoxic and potentially fatalwhen taken in overdose. Foods and medicines that contain high levels ofa chemical called tyramine are dangerous for people taking MAOIs.Tyramine is found in some cheeses, wines, and pickles. The chemical isalso in some medications, including decongestants and over-the-countercold medicine. Mixing MAOIs and tyramine can cause a sharp increase inblood pressure, which can lead to stroke. The combined use of MAOIs andmeperidine (DEMEROL®) or any SSRI compound can result in death.

In addition, prescription anti-depressant therapies such as thoseprovided above may cause significant withdrawal symptoms upontermination of the therapy. Patients may experience a number ofunpleasant withdrawal symptoms such as crying spells, extremerestlessness, dizziness, fatigue, and aches and pains. These withdrawalsymptoms are known as anti-depressant discontinuation syndrome.Anti-depressant discontinuation syndrome is especially associated withtaking PAXIL® or EFFEXOR®. However, any conventional medications fordepression can cause withdrawal symptoms. Anti-depressant withdrawalsymptoms may include the following: anxiety, agitation, depression, moodswings, flu-like symptoms, irritability and aggression, insomnia,nightmares, nausea and vomiting, dizziness, loss of coordination,stomach cramping and pain, electric shock sensations, tremor and musclespasms. Depression and anxiety are also common symptoms when withdrawingfrom anti-depressants. When depression is a withdrawal symptom, it'soften worse than the original depression that led to drug treatment inthe first place. Unfortunately, many people mistake this withdrawalsymptom for a return of their depressive illness and resume medication,creating a vicious circle.

Thus, to avoid the risk of developing adverse effects associated withprescription anti-depressant therapies, it is desirable to reduce theamount (e.g., dose) of a prescription anti-depressant necessary toeffectively treat depression, or preferably replace it altogether or atleast partially with an alternative, which does not cause these adverseeffects. Indeed, the compositions and treatment protocols comprising acombination of therapeutics provides an effective and safe alternative.Furthermore, the compositions and treatment protocols described herein,when used in conjunction with one or more prescription anti-depressanttherapies, may allow patients to reduce the amount of the prescriptionanti-depressant needed to maintain the effectiveness of the treatment,thereby reducing or minimizing unwanted side effects associated with thedrug. In some cases, the patients may completely replace theconventional therapy with an combination therapy without compromisingthe overall efficacy of the treatment of depression. This expectation isbased on the notion that when the composition or the method providedherein is used in conjunction with a conventional therapy it may bepossible to reduce the amount of the medicament to a dose that by itselfis ineffective in treating depression, thereby replacing entirely orpartially a dosage of the medicament. This is particularly useful toavoid or reduce unwanted side effects from the drug (medicament), e.g.,SSRIs, when an effective amount of the drug accompanies adverse effectsin the subject. For example, when used in combination with the methoddescribed herein, an effective dose for a conventional therapeutic agentmay be reduced by 10%, 20%, 30%, 40%, 50% or more, as compared to aneffective dose when the therapeutic agent is used alone. In some cases,the therapy may completely substitute a conventional therapy withoutcompromising the outcome of the treatment.

In some embodiments, the subject diagnosed with depression is receivingor has received a prescription anti-depressant therapy, such as anSSRI-based therapy. In certain situations, it is particularly desirableto change the course of the treatment regimen for one reason or another.As described above, for example, in some cases, the subject is anon-responder. In some cases, a subject receiving a conventional therapymay experience adverse side effects such as those listed above that itmay be desirable to seek an alternative treatment regimen. Under thesecircumstances, the subject may gradually shift from the prescriptionanti-depressant-based therapy to the therapy over a period of time. Forexample, the subject may receive a gradually increasing proportion ofthe therapy in conjunction with a gradually decreasing proportion of theconventional therapy until either the adverse side effects lessen orsubsides, or until the treatment regimen is completely replaced with thetherapy. The changes (e.g., shift) can be made in increments over time,such as weeks to months.

As alluded to above, particularly alarming with respect to aprescription anti-depressant-based therapy is the risk of suicidalideation. There is a danger that, in some people, anti-depressanttreatment will cause an increase, rather than a decrease, in depression.In fact, the U.S. Food and Drug Administration (FDA) requires that allanti-depressant medications include a warning label about the increasedrisk of suicide in children and young adults, e.g., under the age of 24.The suicide risk is particularly great during the first month to twomonths of treatment. In 2004, the FDA looked at published andunpublished data on trials of anti-depressants that involved nearly4,400 children and adolescents. They found that 4 percent of thosetaking anti-depressants thought about suicide or exhibited emergentsuicidal behavior (although no suicides occurred), compared to 2 percentof those receiving placebos (sugar pill).

In response, the FDA decided to adopt a “black box” warning label—themost serious type of warning—on all anti-depressant medications inOctober of 2004. The warning states that there is an increased risk ofsuicidal thinking or attempts in children and adolescents takinganti-depressants. Subsequently, in 2007, the FDA proposed that makers ofall anti-depressant medications extend the warning to include youngadults up through age 24.

Due to the associated risk of suicide, those taking prescriptionanti-depressants are cautioned to be closely observed for suicidalthoughts and behaviors. Monitoring is said to be especially important ifthe subject is undergoing depression medication for the first time or ifthe dose has recently been changed. The patients and family members aregenerally cautioned for “red flags” such as anxiety, insomnia,hostility, and extreme agitation—particularly if the symptoms appearsuddenly or rapidly deteriorate. These risks associated withprescription anti-depressants pose a significant amount of constraintsnot only on the patients but also on their family members andcaretakers. Thus, although results of a comprehensive review ofpediatric trials conducted between 1988 and 2006 suggested that thebenefits of anti-depressant medications likely outweigh their risks tochildren and adolescents with major depression and anxiety disorders,there is a strong incentive—and benefit—in reducing these risks byseeking alternative remedies, that are safer but still effective intreating the disorder.

As noted above, one of the risk factors for increased suicidal ideationis the age of the subject. Children and young adults—those under the ageof 24 are particularly at risk of developing suicidal thoughtsassociated with depression, especially when administered an SSRI.Therefore, it is contemplated that in some embodiments the subject inneed of treatment for depression and will benefit from the therapy is ahuman subject of the ages between 6 and 35 diagnosed with a depressivedisorder, such as MDD. In some embodiments, the subject is between 9 and30 years of age. In some embodiments, the subject is between 13 and 24years of age, such as 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24years old. In certain embodiments, the subject is 24 years old oryounger.

In some embodiments, the subject has been diagnosed with MDD or arelated mood disorder, and is receiving or has received a prescriptionanti-depressant therapy (e.g., an SSRI) and has experienced suicidalideation or at risk thereof due to factors such as a past history ofsuicide attempt. In these situations, the subject may benefit fromswitching to the therapy. Upon determination of such benefits, thesubject may gradually (e.g., in increments) replace a prescriptionanti-depressant drug with the therapy. In some cases, the prescriptionanti-depressant is over time completely weaned off and is replaced withthe therapy. In other cases, the prescription anti-depressant is reducedin dose, frequency or both, but is partially used in combination withthe therapy. In other cases, the guardian of a child in whomanti-depressant therapy is contemplated may choose to initially treatthe child's depression with the therapy since it is less likely toelicit suicidal ideation.

Thus, as generally described above, the therapy may be used inconjunction with a variety of therapies to enhance therapeutic effects.It is contemplated that the combination of therapeutic substancesaccording to the present disclosure will provide at least the level ofefficacy of the commonly used selective serotonin reuptake inhibitordrugs (SSRIs) without being subject to the limitations of that drugclass as described above, and may in fact provide greater efficacythrough synergy with minimal risk and side effects. Combining drugswhich have apparent efficacy as mood stabilizers as well as providinganti-depressant effects may be an alternate mechanism for increasedoverall efficacy in a heterogeneous population of depressed patients.These therapeutic substances are all generally well tolerated, and withdosages kept below certain milligram amounts, especially with folicacid, the preparation should be able to be made as a formulationavailable over-the-counter without prescription.

Moreover, as generally described above, in some cases, it may bebeneficial to use the therapy in combination with a prescriptionanti-depressant-based therapy, either as a single composition or asseparate compositions administered in conjunction to a subject to treata neuropsychiatric condition, such as depression. However, the subjectswho will benefit from the composition and the methods described hereininclude those who choose to avoid prescription anti-depressant therapies(such as SSRIs) prone to causing multiple adverse side effects, thosewho do not respond to a prescription anti-depressant therapy and/orthose who experience an adverse side effect or undesired side effectfrom prescription anti-depressant therapy.

According to certain embodiments, a subject is a human subject sufferingfrom depression, including an MDD or other related mood disorder(s). Thesubject may or may not be already diagnosed with the condition. However,the subject clinically presents one or more symptoms of depression.Alternatively, the subject has not clinically presented one or moresymptoms of the condition but is at risk of developing depression. Forexample, the subject may have a history of episodes of depression ormood disorders. In some cases, the subject may be geneticallypredisposed of one or more such disorders. In some cases, the subject ispregnant, plans to become pregnant or is nursing. In some embodiments,suitable subjects include pediatric populations with one or more of theabove indicated clinical symptoms or risk. The compositions and methodsdescribed herein are particularly useful for treating such a populationbecause most conventional drug therapies available in the market formood disorders (such as prescription anti-depressant) are not suitablefor use for those under the age of 18.

Compositions, Treatment, and Administration

As generally described above, provided herein are methods andcompositions involving a specific combination of therapeutic agents: (1)SAMe or a salt thereof; (2) folic acid, or a salt thereof, or activemetabolite thereof (e.g., methyl folate or folinic acid or a saltthereof); (3) a compound of Formula (I), or salt thereof; (4) one ormore omega fatty acids; and/or (5) vitamin D3. In certain embodiments,this combination is provided in an effective amount. In certainembodiments, this combination is provided in a prophylacticallyeffective amount. Other components, such as Vitamin B12 and/or otheranti-depressants, may optionally be added to the therapeutic regimen. Incertain embodiments, any one of the compositions described herein is amedical food.

More specifically, in one aspect, provided is a composition comprisingS-adenosyl methionine (SAMe), or a salt thereof; and a compound ofFormula (I), or salt thereof. In certain embodiments, the compositionfurther comprises folic acid, or a salt thereof, or active metabolitethereof (e.g., methyl folate or folinic acid or a salt thereof). Incertain embodiments, the composition further comprises one or moreomega-3 fatty acids, or salts thereof. In certain embodiments, thecomposition further comprises vitamin D3.

In another aspect, provided is a composition comprising folic acid, or asalt thereof, or active metabolite thereof (e.g., methyl folate orfolinic acid or a salt thereof); and a compound of Formula (I), or asalt thereof. In certain embodiments, the composition further comprisesS-adenosyl methionine (SAMe), or salt thereof. In certain embodiments,the composition further comprises one or more omega-3 fatty acids, orsalts thereof. In certain embodiments, the composition further comprisesvitamin D3.

In another aspect, provided is a composition comprising one or moreomega-3 fatty acids or, salts thereof; and a compound of Formula (I), ora salt thereof. In certain embodiments, the composition furthercomprises S-adenosyl methionine (SAMe), or salt thereof. In certainembodiments, the composition further comprises folic acid, or a saltthereof, or active metabolite thereof (e.g., methyl folate or folinicacid or a salt thereof). In certain embodiments, the composition furthercomprises vitamin D3.

In another aspect, provided is a composition comprising vitamin D3; anda compound of Formula (I), or a salt thereof. In certain embodiments,the composition further comprises S-adenosyl methionine (SAMe), or saltthereof. In certain embodiments, the composition further comprises folicacid, or a salt thereof, or active metabolite thereof (e.g., methylfolate or folinic acid or a salt thereof). In certain embodiments, thecomposition further comprises one or more omega-3 fatty acids, or saltsthereof.

In another aspect, provided is a composition comprising a compound ofFormula (I), or a salt thereof. In certain embodiments, the compositionfurther comprises folic acid, or a salt thereof, or active metabolitethereof (e.g., methyl folate or folinic acid or a salt thereof). Incertain embodiments, the composition further comprises S-adenosylmethionine (SAMe), or salt thereof. In certain embodiments, thecomposition further comprises one or more omega-3 fatty acids, or saltsthereof. In certain embodiments, the composition further comprisesvitamin D3.

In certain embodiments, the composition comprises S-adenosyl methionine(SAMe), or a salt thereof; folic acid, or a salt thereof, or activemetabolite thereof (e.g., methyl folate or folinic acid or a saltthereof); and a compound of Formula (I), or a salt thereof. In certainembodiments, the composition further comprises one or more omega-3 fattyacids, or salts thereof. In certain embodiments, the composition furthercomprises vitamin D3. In certain embodiments, the composition consistsessentially of S-adenosyl methionine (SAMe), or a salt thereof; folicacid, or a salt thereof, or active metabolite thereof (e.g., methylfolate or folinic acid or a salt thereof); and a compound of Formula(I), or a salt thereof. In certain embodiments, the composition consistsessentially of S-adenosyl methionine (SAMe), or a salt thereof; folicacid, or a salt thereof, or active metabolite thereof (e.g., methylfolate or folinic acid or a salt thereof); a compound of Formula (I), ora salt thereof; and one or more omega-3 fatty acids, or salts thereof.In certain embodiments, the composition consists essentially ofS-adenosyl methionine (SAMe), or a salt thereof; folic acid, or a saltthereof, or active metabolite thereof (e.g., methyl folate or folinicacid or a salt thereof); a compound of Formula (I), or a salt thereof;one or more omega-3 fatty acids, or salts thereof; and vitamin D3.

In certain embodiments, the one or more omega-3 fatty acids or saltsthereof comprises at least 50% EPA. In certain embodiments, the one ormore omega-3 fatty acids or salts thereof comprises at least 60% EPA.

In certain embodiments, the composition is formulated for oraladministration.

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount ofS-adenosyl methionine, or a salt thereof; and a compound of Formula (I),or a salt thereof, to a subject in need thereof. In certain embodiments,the method further comprises administering folic acid, or a saltthereof, or active metabolite thereof (e.g., methyl folate or folinicacid or a salt thereof). In certain embodiments, the method furthercomprises administering one or more omega-3 fatty acids, or saltsthereof. In certain embodiments, the method further comprisesadministering vitamin D3.

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount offolic acid, or a salt thereof, or active metabolite thereof (e.g.,methyl folate or folinic acid or a salt thereof); and a compound ofFormula (I):

or a salt thereof, to a subject in need thereof. In certain embodiments,the method further comprises administering S-adenosyl methionine, or asalt thereof. In certain embodiments, the method further comprisesadministering one or more omega-3 fatty acids, or salts thereof. Incertain embodiments, the method further comprises administering vitaminD3.

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount ofone or more omega-3 fatty acids, or salts thereof; and a compound ofFormula (I), or a salt thereof, to a subject in need thereof. In certainembodiments, the method further comprises administering S-adenosylmethionine, or a salt thereof. In certain embodiments, the methodfurther comprises administering vitamin D3. In certain embodiments, themethod further comprises administering folic acid, or a salt thereof, oractive metabolite thereof (e.g., methyl folate or folinic acid or a saltthereof).

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount ofvitamin D3; and a compound of Formula (I), or a salt thereof, to asubject in need thereof. In certain embodiments, the method furthercomprises administering S-adenosyl methionine, or a salt thereof. Incertain embodiments, the method further comprises administering one ormore omega-3 fatty acids, or salts thereof. In certain embodiments, themethod further comprises administering folic acid, or a salt thereof, oractive metabolite thereof (e.g., methyl folate or folinic acid or a saltthereof).

In another aspect, provided is a method of treating a neuropsychiatriccondition, the method comprising administering an effective amount of acompound of Formula (I), or a salt thereof, to a subject in needthereof. In certain embodiments, the method further comprisesadministering S-adenosyl methionine, or a salt thereof. In certainembodiments, the method further comprises administering one or moreomega-3 fatty acids, or salts thereof. In certain embodiments, themethod further comprises administering folic acid, or a salt thereof, oractive metabolite thereof (e.g., methyl folate or folinic acid or a saltthereof). In certain embodiments, the method further comprisesadministering vitamin D3.

It is contemplated that two or more therapeutic agents described hereinmay be administered together in the same composition or administeredseparately in different compositions. In certain embodiments, two of thetherapeutic agents are administered together in the same composition,and the other therapeutic agent(s) are administered separately in adifferent compositions. In certain embodiments, each of the therapeuticagents may be administered separately in different compositions.

Furthermore, any of the compositions described herein may also comprisea prescription anti-depressant, such as selective serotonin reuptakeinhibitors (SSRIs), serotonin and dopamine reuptake inhibitors (SDRIs),serotonin-norepinephrine reuptake inhibitors (SNRIs),serotonin-noradrenaline-dopamine reuptake inhibitors (SNDRIs),norepinephrine-dopamine reuptake inhibitors (NDRIs), norepinephrine(noradrenaline) reuptake inhibitors (NRIs), monoamine oxidase inhibitors(MAOIs), selective serotonin reuptake enhancers (SSREs), melatonergicagonists, tryptamines, tricyclic anti-depressants, or atypicalant-depressants, as described herein.

In certain embodiments, the prescription anti-depressant is a selectiveserotonin reuptake inhibitor (SSRI). In certain embodiments, the SSRI isselected from the group consisting of citalopram, escitalopram,fluoxetine, fluvoxamine, paroxetine, sertraline fenfluramine,norfenfluramine, dapoxetine, femoxetine, and indalpine.

In certain embodiments, the prescription anti-depressant is adopaminergic anti-depressant. In certain embodiments, the dopaminergicanti-depressant is selected from the group consisting of amineptine,burpoprion, methamphetamine, methylphenidate, nomifensine, pramipexole,ropinirole, and vanoxerine (GBR-12909).

In certain embodiments, the prescription anti-depressant is aserotonin-norepinephrine reuptake inhibitor (SNRI). In certainembodiments, the SNDRI is selected from the group consisting ofbrasofensine, tesofensine, DOV 21,947 and DOV 102,677.

In certain embodiments, the prescription anti-depressant is anorepinephrine-dopamine reuptake inhibitor (NDRI). In certainembodiments, NDRI is bupropion, reboxetine or radafaxine.

In certain embodiments, the prescription anti-depressant is a monoamineoxidase inhibitor (MAOI). In certain embodiments, the MAOI is selectedfrom the group consisting of isocarboxazid, moclobemide, phenelzine,tranylcypromine, selegiline, emsam, rasagiline, nialamide, iproniazid,iproclozide, toloxatone, linezolid, and Zyvox®.

In certain embodiments, the prescription anti-depressant is atryptamine.

In certain embodiments, the prescription anti-depressant is a tricyclicanti-depressant having serotonergic activity. In certain embodiments,the tricyclic anti-depressant is selected from clomipramine andamoxapine.

In certain embodiments, the prescription anti-depressant is an agenthaving serotonergic activity. In certain embodiments, anti-depressanthaving serotonergic activity is selected from the group consisting ofclomipramine, amoxapine, trazadone, olanzapine and ziprasidone.

The composition may optionally comprise a pharmaceutically acceptableexcipient. Suitable examples of excipients include, but are not limitedto, anti-adherents, binders, coatings, disintegrants, fillers anddiluents, flavours, colours, glidants, lubricants, preservatives,sorbents, and sweeteners.

Anti-adherents are generally used to reduce the adhesion between thepowder (granules) and the punch faces and thus prevent sticking totablet punches. Most commonly used is magnesium stearate.

Binders hold the ingredients in a tablet together, and ensure thattablets and granules can be formed with required mechanical strength,and give volume to low active dosis tablets. Exemplary binders include,but are not limited to, starches, sugars, cellulose or modifiedcellulose such as microcrystalline cellulose, hydroxypropyl cellulose,lactose, or sugar alcohols like xylitol, sorbitol or maltitol. Bindersare typically classified according to their application. For example,solution binders are dissolved in a solvent (for example, water oralcohol can be used in wet granulation processes). Non-limiting examplesinclude gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone,starch, sucrose and polyethylene glycol. By contrast, dry binders areadded to the powder blend, either after a wet granulation step, or aspart of a direct powder compression formula. Non-limiting examplesinclude cellulose, methyl cellulose, polyvinylpyrrolidone, andpolyethylene glycol.

Tablet coatings protect tablet ingredients from deterioration bymoisture in the air and make large or unpleasant-tasting tablets easierto swallow. For most coated tablets, a hydroxy propylmethylcellulose(HPMC) film coating is used which is free of sugar and potentialallergens. Occasionally, other coating materials are used, for examplesynthetic polymers, shellac, corn protein zein or other polysaccharides.Capsules are coated with gelatin.

Coatings may be used for purposes of changing the dissolution rates ofactive species. For examples, enteric coatings can be used to controlthe rate of drug release and determine where the drug will be releasedin the digestive tract.

Disintegrants expand and dissolve when wet causing the tablet to breakapart in the digestive tract, releasing the active ingredients forabsorption. Disintegrant types include water uptake facilitators andtablet rupture promoters. They ensure that when the tablet is in contactwith water, it rapidly breaks down into smaller fragments, therebyfacilitating dissolution. Examples of disintegrants include, withoutlimitation, crosslinked polyvinyl pyrrolidone, sodium starch glycolate,sodium bicarbonate, and crosslinked sodium carboxymethyl cellulose(crosscarmellose).

Fillers fill out the size of a tablet or capsule, making it practical toproduce and convenient for the consumer to use. By increasing the bulkvolume, the fillers make it possible for the final product to have theproper volume for patient handling. A suitable filler must be inert,compatible with the other components of the formulation,non-hygroscopic, soluble, relatively inexpensive, compactible, andpreferably tasteless or pleasant tasting. For example, plant cellulose(pure plant filler) is a popular filler in tablets or hard gelatincapsules. Dibasic calcium phosphate is another popular tablet filler. Arange of vegetable fats and oils can be used in soft gelatin capsules.Other examples of fillers include, without limitation: lactose, sucrose,glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate.

Flavours can be used to mask unpleasant tasting active ingredients andimprove the likelihood that the patient will complete a course ofmedication. Flavourings may be natural (e.g., fruit extract) orartificial.

Colours are added to improve the appearance of a formulation. Colourconsistency is important as it allows easy identification of amedication.

Glidants are used to promote powder flow by reducing interparticlefriction and cohesion. These are used in combination with lubricants asthey have no ability to reduce die wall friction. Examples includecolloidal silicon dioxide, talc, and magnesium carbonate.

Lubricants prevent ingredients from clumping together and from stickingto the tablet punches or capsule filling machine. Lubricants also ensurethat tablet formation and ejection can occur with low friction betweenthe solid and die wall. Common minerals like talc or silica, and fats,e.g., vegetable stearin, magnesium stearate or stearic acid are the mostfrequently used lubricants in tablets or hard gelatin capsules.

Some typical preservatives used in formulations include antioxidantslike vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium;the amino acids cysteine and methionine; citric acid and sodium citrate;and synthetic preservatives such as methyl paraben and propyl paraben.

Sorbents may be used for tablet/capsule moisture-proofing by limitedfluid sorbing (taking up of a liquid or a gas either by adsorption or byabsorption) in a dry state.

Sweeteners may be added to make the ingredients more palatable,especially in chewable tablets such as antacid or liquids like coughsyrup.

Any of the agents described herein can be administered using any amountand any route of administration effective for treatment. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of theinfection, the particular composition, its mode of administration, itsmode of activity, and the like.

Therapeutic agents are typically formulated in dosage unit form for easeof administration and uniformity of dosage. It will be understood,however, that the total daily usage of the compositions will be decidedby the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any particularsubject will depend upon a variety of factors including the conditionbeing treated and the severity of the condition; the activity of thespecific agent employed; the specific composition employed; the age,body weight, general health, sex and diet of the subject; the time ofadministration, route of administration, and rate of excretion of thespecific agent employed; the duration of the treatment; drugs used incombination or coincidental with the specific agent employed; and likefactors well known in the medical arts.

Therapeutic agents provided herein can be administered by any route,including oral, intravenous, intramuscular, intra-arterial,intramedullary, intrathecal, subcutaneous, intraventricular, transdermal(e.g., patches), interdermal, rectal, intravaginal, intraperitoneal,topical (as by powders, ointments, creams, and/or drops), mucosal,nasal, bucal, enteral, sublingual; by intratracheal instillation,bronchial instillation, and/or inhalation; and/or as an oral spray,nasal spray, and/or aerosol. In general the most appropriate route ofadministration will depend upon a variety of factors including thenature of the agent, the condition of the subject (e.g., whether thesubject is able to tolerate oral administration), etc. The preferredroute of administration is oral administration.

The exact amount of an agent required to achieve a therapeuticallyeffective or prophylactically effective amount will vary from subject tosubject, depending, for example, on species, age, and general conditionof a subject, severity of the side effects or condition, identity of theparticular compound(s), mode of administration, and the like. Thedesired dosage can be delivered three times a day, two times a day, oncea day, every other day, every third day, every week, every two weeks,every three weeks, or every four weeks. In certain embodiments, thedesired dosage can be delivered using multiple administrations (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or more administrations).

For example, in a non-limiting embodiment, the therapy may be formulatedas one or more tablets or capsules for oral administration. Forinstance, a tablet or capsule may contain one or more of the followingcomponents such that the components are administered together, either inone or more compositions, as part of the therapy:

-   -   (1) about 200 mg to about 2000 mg of SAMe, or a salt thereof        (e.g., about 400 mg to about 1600 mg, or about 800 mg to about        1600 mg of SAMe or a salt thereof);    -   (2) about 0.5 mg to about 5 mg of folic acid, or a salt thereof        (e.g., about 1 mg to about 3 mg of folic acid or a salt        thereof); and/or about 5 mg to about 45 mg of methyl folate, or        a salt thereof (e.g., about 5 mg to about 20 mg of methyl folate        or a salt thereof) and/or about 5 mg to about 15 mg of folinic        acid, or a salt thereof (e.g., about 5 to about 10 mg of folinic        acid, or a salt thereof); and    -   (3) about 50 mg to about 1000 mg of a compound of Formula (I),        or salt thereof;    -   (4) about 500 mg to about 5 g of one or more omega-3 fatty        acids, or salts thereof, e.g., rich in EPA (e.g., about 800 mg        to about 1600 mg of one or more omega-3 fatty acids, or salts        thereof, rich in EPA); and/or    -   (5) about 500 IU to about 2000 IU, inclusive, of vitamin D3.

In certain preferred embodiments, a tablet or capsule may contain one ormore of the following components such that the components areadministered together, either in one or more compositions, as part ofthe therapy:

-   -   (1) about 200 mg to about 2000 mg of SAMe, or a salt thereof        (e.g., about 400 mg to about 1600 mg, or about 800 mg to about        1600 mg of SAMe, or a salt thereof);    -   (2) about 5 mg to about 45 mg of methyl folate, or a salt        thereof (e.g., about 5 to about 20 mg of methyl folate, or a        salt thereof);    -   (3) about 50 mg to about 500 mg of a compound of Formula (I), or        salt thereof;    -   (4) about 500 mg to about 5 g of one or more omega-3 fatty        acids, or salts thereof, e.g., rich in EPA (e.g., about 800 mg        to about 1600 mg of one or more omega-3 fatty acids, or salts        thereof, rich in EPA); and/or    -   (5) about 800 IU to about 1200 IU, inclusive, of vitamin D3.

The therapy may be administered once, twice or three times daily,depending on total recommended daily dosage of the therapy combination,the subject, and the condition to be treated. For example, a subject inneed may take the therapy 1 to 6 times daily, for example, 1, 2, 3, 4,5, 6 times daily, depending on the body weight, age, and other clinicalcriteria.

Kits

The therapy described herein is readily adaptable for distribution inthe form of a kit. A kit is typically packaged individually in acontainer. A kit may include each of the therapy components describedherein premeasured and/or mixed together in a fashion convenient foradministration, e.g., formulated into one or more capsules, tablets,syrup, transdermal patches, etc. The kit typically includes instructionsfor use, which may be on a separate piece of medium (e.g., on a sheet ofpaper), or printed upon a container itself, or on the surface of apackage. Alternatively, or in addition, the instructions may be madeavailable separately via, for example, online sources. The kit comprisesat least one unit dosage form of the composition. Typically, however,the kit contains a supply of the therapy to be taken for a predeterminedduration of time, e.g., a 7-day supply, 14-day supply, 30-day supply,60-day supply, or 90-day supply of the therapy.

In some embodiments, the kit also includes prescribing information.

ADDITIONAL DEFINITIONS

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an”, as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B”, when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” will refer tothe inclusion of exactly one element of a number or list of elements. Ingeneral, the term “or” as used herein shall only be interpreted asindicating exclusive alternatives (i.e., “one or the other but notboth”) when preceded by terms of exclusivity, such as “either,” “oneof,” “only one of,” or “exactly one of.” “Comprising,” “consisting of,”and “consisting essentially of”, when used in the claims, shall have itsordinary meaning as used in the field of patent law.

As used herein, the term “salt” refers to those salts which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, S. M. Berge et al., describespharmaceutically acceptable salts in detail in J. PharmaceuticalSciences (1977) 66:1-19. Pharmaceutically acceptable salts include thosederived from suitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

A “subject” to which administration is contemplated includes, but is notlimited to, a mammal, including humans (i.e., a male or female of anyage group, e.g., a pediatric subject (e.g, infant, child, adolescent) oradult subject (e.g., young adult, middle-aged adult or senior adult)),other primates (e.g., cynomolgus monkeys, rhesus monkeys); commerciallyrelevant mammals such as cattle, pigs, horses, sheep, and goats; anddomestic mammals such as cats and dogs. The subject may also be apregnant female.

As used herein, the terms “condition,” “disease,” and “disorder” areused interchangeably to refer to an impaired biological, clinical,and/or psychiatric condition in a subject.

The terms “substance,” “drug,” “agent,” “therapeutic,” “therapeuticagent,” “medicine,” and “medicament” are used interchangeably herein.

The terms “treating,” “treatment,” and “promotion,” are used herein tomean providing a subject in need with a “therapy” to obtain all or anyof the desired results of a therapy. The term “therapy” as used hereingenerally means any biological or psychiatric application or treatmentused to obtain a desired pharmacologic, biologic, physiologic and/orpsychologic effect. The effect may be prophylactic in terms ofcompletely or partially preventing a disease or symptom thereof and/ormay be therapeutic in terms of a partial or complete cure for a diseaseand/or adverse effect attributable to the disease. Therapeutic effectsshall include: (a) preventing a condition from occurring in a subjectwhich may be predisposed to the condition but has not yet been diagnosedas having it; (b) inhibiting a condition, i.e., arresting itsdevelopment; and/or (c) relieving a condition, i.e., causing regressionof the condition.

As used herein, unless otherwise specified, the terms “prevent,”“preventing” and “prevention” contemplate an action that occurs before asubject (e.g., such as a pregnant subject) begins to suffer from thecondition, which inhibits or reduces the severity of the condition.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thecondition in a subject who has already suffered from the condition. Theterms encompass modulating the threshold, development and/or duration ofthe condition, and/or changing the way that a subject responds to thecondition.

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound may vary depending on such factors as the desiredbiological endpoint, the pharmacokinetics of the compound, the diseasebeing treated, the mode of administration, and the age, health, andcondition of the subject. An effective amount encompasses therapeuticand prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of an agent or combination of agents is an amountsufficient to provide a therapeutic benefit in the treatment ormanagement of a condition, or to delay or minimize one or more symptomsassociated with the condition. A therapeutically effective amount of anagent or combination of agents means an amount of the therapeutic agent,alone or in combination with other therapies, which provides atherapeutic benefit in the treatment or management of the condition. Theterm “therapeutically effective amount” can encompass an amount thatimproves overall therapy, reduces or avoids symptoms or causes of thecondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, a “prophylactically effective amount” of an agent orcombination of agents is an amount sufficient to prevent a condition, orone or more symptoms associated with the condition, or prevent itsrecurrence. A prophylactically effective amount of an agent orcombination of agents means an amount of therapeutic agent, alone or incombination with other agents, which provides a prophylactic benefit inthe prevention of the disease, disorder or condition. The term“prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

As used herein, “suffer”, “suffers,” “suffering from” or “having” refersto a subject diagnosed with a condition. As used herein, “likely tosuffer from” or “likely to have” refers to a subject who has not beendiagnosed with a particular condition by a medical practitioner, but hasa predisposition for (e.g., genetic and/or physiologic predisposition),or exhibits signs or symptoms of, the condition.

As used herein, “in combination” or “in conjunction” (as in“administered in conjunction with” or “administered together”) refers tothe combining of two or more of the agents such that the therapeuticeffects from the agents are overlapping in time and/or target (e.g.,cells, tissues) in vivo. In some embodiments, the two or more agents areadministered together in the same composition. In some embodiments, thetwo or more agents are administered together in separate compositions(i.e., “administered separately”). In certain embodiments, the two ormore agents are administered together at the same time (i.e.,“administered simultaneously”). In certain embodiments, the two or moreagents are administered together one after the other (i.e.,“administered sequentially”).

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one act,the order of the acts of the method is not necessarily limited to theorder in which the acts of the method are recited.

Each of the foregoing patents, patent applications and references thatare recited in this application are herein incorporated in theirentirety by reference, particularly for the teaching referenced herein.

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Other Embodiments

All patents, patent applications, and literature references cited hereinare incorporated herein by reference.

The foregoing has been a description of certain non-limitingembodiments. Those of ordinary skill in the art will appreciate thatvarious changes and modifications to this description may be madewithout departing from the spirit or scope of the present disclosure, asdefined in the following claims.

What is claimed is:
 1. A method of treating a neuropsychiatriccondition, or for promoting wellness and/or energy, the methodcomprising administering an effective amount of S-adenosyl methionine(SAMe), or a salt thereof; methyl folate, or a salt thereof; and acompound of Formula (I):

or a salt thereof, wherein: R is hydrogen or —C(═O)R^(A), wherein R^(A)is unsubstituted C₁₀₋₁₈ alkyl; and —C(═O)R^(B) is of the formula:

to a subject in need thereof.
 2. The method of claim 1, wherein thecompound of Formula (I) is of the formula:

or a salt thereof.
 3. The method of claim 1, wherein the compound ofFormula (I), or salt thereof, is provided in a range of between about 50mg to about 1000 mg, inclusive.
 4. The method of claim 1, whereinS-adenosyl methionine, or a salt thereof, is provided in a range ofbetween about 200 mg to about 2000 mg, inclusive.
 5. The method of claim1, wherein methyl folate, or a salt thereof, is provided in a range ofbetween about 1 mg to about 45 mg, inclusive.
 6. The method of claim 1,further comprising administering one or more omega-3 fatty acids, orsalts thereof.
 7. The method of claim 6, wherein one or more omega-3fatty acids, or salts thereof, is provided in a range of between about500 mg to about 5 g, inclusive.
 8. The method of claim 6, wherein theone or more omega-3 fatty acids, or salts thereof, comprises at least50% EPA.
 9. The method of claim 1, further comprising administeringvitamin D3.
 10. The method of claim 9, wherein the vitamin D3 isprovided in a range of about 500 IU to about 2000 IU, inclusive.
 11. Themethod of claim 1, further comprising administering vitamin B_(12.) 12.The method of claim 1, wherein S-adenosyl methionine (SAMe), or a saltthereof; methyl folate, or a salt thereof; and a compound of Formula(I), or a salt thereof, are each administered separately in differentcompositions.
 13. The method of claim 1, wherein S-adenosyl methionine(SAMe), or a salt thereof; methyl folate, or a salt thereof; and acompound of Formula (I), or a salt thereof, are administered together inthe same composition.
 14. The method of claim 1, wherein theneuropsychiatric condition is selected from mood disorders or conditionscharacterized by atypical mood.
 15. The method of claim 14, wherein themood disorders are selected from the group consisting of depression,Bipolar Disorder, and Anxiety Disorder.
 16. The method of claim 15,wherein the depression is Major Depressive Disorder.
 17. The method ofclaim 14, wherein the condition characterized by atypical mood isselected from the group consisting of stress, hormonal mood swings, MildCognitive Impairment, substance-induced mood disorders, dementia,Alzheimer's disease, Parkinson's disease, Huntington's disease, andpsychotic disorders.
 18. The method of claim 17, wherein the hormonalmood swings are mood swings during pregnancy, during post-partum, duringpuberty, or during menopause, or are a result of a PremenstrualDysphoric Disorder condition.
 19. The method of claim 17, wherein thepsychotic disorder is selected from the group consisting ofSchizoaffective Disorder, Schizophrenia, Delusional Disorder, andPsychotic Disorder Not Otherwise Specified.
 20. The method of claim 1,wherein the method is for treating depression.
 21. The method of claim1, wherein the compound of Formula (I), or salt thereof, is provided ina range of between about 100 mg to about 500 mg, inclusive.